GB2054555A - Pyrazolyl amino imidazolines - Google Patents

Pyrazolyl amino imidazolines Download PDF

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GB2054555A
GB2054555A GB7926299A GB7926299A GB2054555A GB 2054555 A GB2054555 A GB 2054555A GB 7926299 A GB7926299 A GB 7926299A GB 7926299 A GB7926299 A GB 7926299A GB 2054555 A GB2054555 A GB 2054555A
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hydrogen
amino
methyl
loweralkyl
pyrazolyl
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D231/38—Nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D231/38—Nitrogen atoms
    • C07D231/40—Acylated on said nitrogen atom

Abstract

Pyrazine derivatives of the formula <IMAGE> wherein R1 and R2 are hydrogen atoms or are selected from various defined organic groups, R3 is hydrogen, halogen, loweralkyl or aryl, and R4 is hydrogen, acyl, amino or loweralkyl, and the pharmaceutically acceptable acid addition salts thereof, may be used as anti-inflammatory, antihypertensive or diuretic agents.

Description

SPECIFICATION Pyrazolyl amino imidazolines This invention relates to pyrazolyl amino imidazolines.
Rheumatic conditions affect humans and animals, these conditions involving swelling, decreased mobility, tenderness, pain, and fever. While anti-inflammatory agents are presently available which are effective in symptomatic treatment of conditions such as degenerative joint diseases, rheumatoid arthritis, rheumatoid spondylitis, and the like such agents are not entirely effective in stopping the progression of the disease. The availability of additional antiinflammatory agents is therefore desirable. The present invention provides a number of such anti-inflammatory agents as well as antihypertensive and diuretic agents.
This invention relates to compounds represented by the formula
wherein R' and R2 are hydrogen, loweralkyl, lowercycloalkyl
where X is H, halo, loweralkyl, lowercycloalkyl, haloalkyl, SO2NH2, NO2, NH2, OH, alkoxy, C00H, alkoxycarbonyl, cycloalkoxy carbonyl, aminocarbonyl, diloweralkylaminocarbonyl or
wherein n is 4 or 5, R3 is H, halogen or aryl, and R4 is H, acyl, amino or loweralkyl.
The term "loweralkyl" refers to straight or branched chain alkyl groups having from 1 to 6 carbon atoms, i.e., methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tertbutyl, rkpentyl, rr hexyl, and the like.
The term "aryl" as used herein refers to phenyl and naphthyl.
The term "acyl", as used herein, refers to acyl groups represented by the formula
wherein R is loweralkyl, i.e., acetyl, propionyl, butyryl, and the like or phenyl.
The term "pharmaceutically acceptable salts" refers to non-toxic acid addition salts prepared by reacting the base with a suitable organic or inorganic acid. Representative salts include the hydrochloride, hydrobromide, sulfate, bisulfate, acetate, oxylate, valerate, oleate, palmitate, stearate, laurate borate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartate, and the like.
The compounds of this invention exhibit anti-inflammatory activity and are generally administered to mammalian patients in dosages of from about 5 to 200 milligrams per kilogram (mg/kg) of body weight daily, either in single or divided doses over a 24 hour period.
The compounds of the present invention can be prepared by two methods, as illustrated below.
In the first method a 1,3-disubstituted-5-aminopyrazole (1) is reacted with benzoyl isothiocyanate to produce N(1,3-disubstituted-5-pyrazolyl)-N-benzoyl thiourea (2). This product reacts with sodium hydroxide to produce (1,3-disubstituted-5-pyrqazolyl) thiourea (3) which in turn reacts with methyl iodide to produce N(1,3-disubstituted-5-pyrazolyl)-5-methyl isothiourea hydroiodide (4). This compound then reacts with ethylene diamine to produce 2-(1,3-disubstituted-5pyrazolyl(amino-2-imidazoline (5), which is treated with a halogen (Br2, C12, or 12) to produce 2(4-Halo-1 , 3-d isubstituted-5-pyrazolyl)a m ino-2-imidazoline.
In the second method, compound (1) is reacted with 1-acetyl-2-imidazolidinone to produce 1acetyl-2-(1 ,3-disubstituted 5-pyrazolyl)amino-2-imidazoline (7). The acetyl group is removed with HCI in methanol to produce the compound 5 which is halogenated as above to produce compound 6.
The preferred method of preparation is represented the second method, described above.
Representative compounds which can be prepared are exemplified in the following examples.
Example I 1 -Acetyl-2(34sopropyl 1 -methyl-5-pyrazolyl) amin o-2-imidazoline 5-amino-3-isopropyl-1-methyl pyrazole (described in British Patent 1,057,740) (19.3 g) was dissolved in 180 ml. phosphorus oxychloride (POCl3). 1-Acetyl-2-imidazolidinone (J. Chem Soc 1964, 178) (20.1 g) was added. This reaction mixture was stirred at 55 for 40 hr. The solvents were concentrated in vacuum, ice and methylene chloride were added and the mixture neutralized with 25% sodium hydroxide in water. The methylene chloride layer was dried over MgSO4 and then concentrated and the residue crystallized from isopropyl alcohol and ether to give 12.73 g of product, mp 145"-147"C.
Example II 2(2-Isopropyl-1-methyl-5-pyrazolyl)-amino-2-imidazoline 1-Acetyl-2(3-isopropyl-1-methyl-5-pyrazolyl)-amino-2-imidazoline (6.21 g.), 120 ml. methanol and 2 drops concentrated hydrochloric acid were mixed and refluxed 16 hr. The solution was then concentrated and the residue treated with CHCl3 and KHCO3 solution. The CHCl3 solution was dried over MgS04, concentrated and the residue crystallized from isopropyl alcohol and ether to give 4.50 g. of product, mp 163"-165"C.
Analyzed for C10Ha7N5: theoretical; C = 57.94, H = 8.28, N = 33.79 Found; C = 57.83, H=8.45, N=33.58 Example III 2(4-Bromo-3-isopropyI- l-methyl-5-pyrazolyl)amino-2-imidazoline hydrobromide 2(3-isopropyl-1-methyl-5-pyrazolyl)-amino.2-imidazoline (6.00 g.) was dissolved in 30 ml.
acetic acid. A solution of 4.55 g. bromine in 10 ml. acetic acid was added dropwise, while cooling, until the color of Br2 pe sisted. The solution was concentrated in vacuum and the residue crystallized from isotropyl alcohol to give 7.85 g. product, mp 225"-226"C, decomposed.
Analysed for C1OH17Br2N5: Theoretical; C = 32.72, H = 4.66, N = 19.07 Found; C = 32.78, H = 4.72, N = 19.24.
Example IV [1-(3-Methylbutyl)-3-methyl-5-pyrazolyl] thiourea 1-(3-methylbutyl-3-methyl-5-aminopyrazole (British Patent 1,057,740) (21.2 g.) was dissolved in 560 ml. benzene. Benzoyl isothiocyanate (21.19 g.) was added dropwise and then the solution was refluxed for 1 hr. The solvent was evaporated in vacuum to yield the intermediate benzoyl pyrazolyl thiourea. This compound was hydrolyzed by refluxing in 100 ml. 10% sodium hydroxide for 20 minutes. Then the mixture was cooled and acidified to a pH of 4 with hydrochloric acid. The resulting solid was filtered, washed with water, and then treated with concentrated ammonia. After stirring 5 minutes the solid was filtered, washed with water, and crystallized from an ethanol-hexane mixture to give 23.0 g. product, mp 173-1 76 C.
Example V N[1-(3-Methylbutyl)-3-methyl-5-pyrazolyl]-S-methyl isothiourea h ydroiodide [1-(3-methylbutyl)-3-methyl-5-pyrazolyl] thiourea (23.0 g.) was dissolved in 250 ml. ethanol and 15.62 g. methyl iodide and refluxed for 4 hours. The ethanol was concentrated in vacuum and ether added to get 29.3 g. product, mp 128-131"C.
Example VI 2f 1 -(3-Methylbutyl)-3-meth yl. 5.pyrazolylj amino-2-imidazoline N[1-(3-methylbutyl)-3-methyl-5-pyrazolylj-S-methyl isothiourea hydroiodide (29.0 g.) was suspended in 1 60 ml. n-propyl alcohol. Ethylene diamine (10.2 g.) was added and the solution was refluxed 1 8 hrs. The solvent was concentrated in vacuum and the residue was treated with KHCO3 in water. The resulting solid was recrystallized from CHCI3-ether mixtures to obtain 14.3 g. product, mp 104-106"C.
Analyzed for C12H21N5: Theoretical; C = 61.24, H = 9.03, N = 29.76, Found; C = 61.40, H = 9.33, N = 29.69 Example VII 2[4-Bromo- 1 -(3-methylbutylJ-3-methyl-5-pyrazolyl]amino-2-imidazoline hydrochloride 2[1-(3-methylbutyl)-3-methyl-5-pyrazolyl] amino-2-imidazoline (6.00 g.) in 35 ml. acetic acid was treated with a solution of 4.10 g. bromine in 10 ml. acetic acid, added dropwise, the solution was then concentrated and the residue treated with chloroform, water, and potassium bicarbonate. The CHCI3 phase was dried over MgSO4 and concentrated. The residue was dissolved in isopropyl alcohol and acidified with HCI. On adding ether, 7.06 g. product, mp 180-182"C crystallized out.
Analyzed for O12H21BrOlN5: Theoretical; C = 41.15, H = 6.03, N = 19.98 Found; C=41.19, H=6.21, N=20.33 Example VIII 1 -Acetyl-2-( 1 -phenyl-5-pyrazolyl)-amino-2-imidazoline 5-Amino-1-phenylpyrazole (6.00 g.), and 1-acetyl-2-imidazolidinone (5.50 g.) were reacted as described in Example I to give 4.95 g. of product, mp 157-159"C.
Analyzed for C,4H15N50: Theoretical; C = 60.40, H = 5.85, N = 25.11 Found; C = 60.65, H = 5.74, N = 24.75 Example IX 2-( 1 -Phenyl-5-pyrazolyl)-amino-2-imidazoline Acetyl-2(1-phenyl-5-pyrazolyl)-amino-2-imidazoline (15.1 g.) was treated with HCI in methanol as described in Example II to give 12.5 g. product mp 206-208"C. The hydrochloride, made with HCI in isopropyl alcohol had a mp of 232-234 C.
Analyzed for O12H14OlN5: Theoretical; C = 54.70, H = 5.36, N = 26.55 Found; C = 54.91, H = 5.41, N = 26.69 Example X 2-(4-Bromo-1-phenyl-5-pyrazolyl)-amino-2-imidazoline hydrochloride 2-(1-phenyl-5-pyrazolyl)-amino-2-imidazoline (5.00 g.) and 3.85 g. bromine were reacted as described in Example VII to give 6.02 g. of product, mp 251-253 C.
Analyzed for C12H13BrCINs: Theoretical; C = 42.02, H = 3.83, N = 20.50 Found; C = 42.21, H = 3.85, N = 19.81 Example XI 1 -Acetyl-2( 1 -isopropyl-3-methyl-5-pyrazolyl)amino-2-imidazoline 5-amino-1-isopropyl-3-methylpyrazole (J. Gen. Chem. USSR 31 234, 1961) (19.3 g.) and 1acetyl-2-imidazolidinone (20.1 g.) were reacted as described in Example I to give 12.73 9. of product, mp 145-147 C.
Example XII 2-(7-lsopropyl-3-methyl-5-pyrazolyl) amino-2-imidazoline 1-acetyl-2-(1-isopropyl-3-methyl-5-pyrazolyl) amino-2-imidazoline (14.0 g.) was treated with HCI in methanol as described in Example II to give 9.05 g of product, mp 173-1 75 C.
Analyzed for CloH17Ns: Theoretical; C = 57.94, H = 8.28, N = 33.79 Found; C = 57.76, H = 8.44, N = 33.93 Example XIII 2-(4-Bromo-1-isopropyl-3-methyl-5-pyrazolyl)amino-2-imidazoline hydrochloride 2-(1-isopropyl-3-methyl-5-pyrazolyl)amino-2.imidazoline (6.00 g.) was treated with 4.60 g. of bromine as described in Example VII to give 8.26 9. product, mp 235-256 C; decomposed.
Analyzed for C,OH,7CIBrN5: Theoretical; C = 37.21, H = 5.32, N = 21.70 Found; C=37.17, H=5.26, N=21.62.
Example XIV 2-(1-Cyclohexyl-5-pyrazolyl)-amino-2-imidazoline 2-(1 -phenyl-5-pyrazolyl)-amino-2-imidazoline (9.00 9.) in 250 ml. methanol was hydrogenated at 3 atmospheres and 60 C over 5% Rh/AI203 catalyst. The catalyst was filtered, the solvent removed in vacuum and the residue crystallized from benzene to give 4.0 9. of product, mp 183-1 85'C.
Analyzed for Ca2HrgN5 Theoretical; C = 61.78, H = 8.21, N = 30.02 Found; C = 61.63, H = 8.33, N = 29.63 Example XV 2-(4-Brom o-1 -cycloh exyl-5-pyrazolyl)-amino-24midazoline hydrochloride 2-(1-cyclohexyl-5-pyrazolyl)-amino-2-imidazoline (6.40 g.) was treated with 14.30 9 bromine as described in Example VII to give 8.10 9. product, mp 242-244 C decomposed.
Analyzed for C,2H,9BrCIN5: Theoretical; C = 41.30, H = 5.49, N = 20.08 Found, C= 41 .18, H = 5.09, N = 19.65 Example XVI 5-Amino- 1, 3-di-isopropyl pyrazole 4-methyl-3-keto pentanitrile (13.0 9) (Can. J. Chem. 48, 2110, 1970) (13.09.), isopropyl hydrazine (10.0 9.) and 50 ml. ethanol were refluxed for 4 hrs. The solvent was removed in vacuum and the residue crystallized from cyclohexane and ether to produce 13.88 9. of product, mp 62-65 C.
Analyzed for CgH17N3: Theoretical; C = 64.63, H = 10.25, N = 25.13 Found; C = 64.67, H=10.51, N=25.4O Example XVII 1-Acetyl-2-(1,3-di-isopropyl-5-pyrazolyl) amino-2-imidazoline 5-Amino-1 ,3-di-isopropyl pyrazole (13.5 9.) and 1-acetyl-2-imidazolidinone (12.2 g.) were reacted as described in Example I to give 13.01 9. of product, mp 139-140 C.
Example XVIII 2-( 1, 3-Di-isopropyl-5-pyrazolyl)-amino-2-imidazoline 1-Acetyl-3-(1 ,3-di-isopropyl-5-pyrazolyl)amino-2-imidazoline (13.0 9.) was treated with HCI in methanol as described in Example II to give 6.60 g. of product, mp 159-161 C.
Analyzed for C,2H2,N5: Theoretical; C = 61.24, H = 9.00, N = 29.76 Found; C = 61.04, H = 9.21, N = 29.93 Example XIX 2-(4-Bromo- 1, 3-di-isopropyl-5-pyrazolyl)amino-2-imidazoline hydrobromide 2-(1 ,3-Di-isopropyl-5-pyrazolyl)-amino-2-imidazoline (2.00 9.) was treated with 1.5 9. bromine as described in Example Ill to give 2.61 g. of product, mp 220-221 C., decomposed.
Analyzed for C12H21Br2n5: Theoretical; C = 36.47, N = 5.35, N = 17.73, Br = 40.45 Found; C = 36.71, H = 5.56, N = 17.60, Br = 40.36 Example XX (1, 3-Diphenyl-5-pyrazolyl) thiourea 1 ,3-Diphenyl-5-amino pyrazole (117.5 9.) and benzoyl isothiocyanate (89.65 9.) were reacted as described in Example IV to give 11 9.8 9. of product, mp 198-201 C.
Example XXI N-( 1, 3-Diphenyl-5-pyrazolyl)-S-methyl isothiourea hydroiodide (1 ,3-Diphenyl-5-pyrazolyl) thiourea (119.7 9.) and 63.9. methyl iodide were reacted as described in Example Vto give 156.1 9. of product, mp 178-182 C.
Example XXII 2(1, 3-Diphenyl-5-pyrazolyl) amino-2-imidazoline N(1,3-Diphenyl-5-pyrazolyl)-S-methyl isothiourea hydroiodide (43.6 9.) and ethylene diamine (12.0 9.) were reacted as described in Example VI to give 26.0 9. of the product, mp 228-230 C.
Analyzed for C,8H,7N5: Theoretical; C = 71.29, H = 5.61, N = 23.10 Found; C = 71.20, H = 5.64, N=23.16 Example XXIII 2(4-Bromo-1,3-diphenyl-5-pyrazolyl) amino-2-imidazoline hydrobromide 2(1 ,3-diphenyl-5-pyrazolyl) amino-2-imidazoline (6.0 9.) was treated with 3.2 9. bromine as described in Example Ill to give 8.85 9. of the product, mp 2735C. decomposed.
Analyzed for C18H17Br2N5: Theoretical; C = 46.80, H = 3.71, N = 15.12 Found; C=47.19, H=3.83, N=14.98 Example XXIV (1, 3-Dimethyl-5-pyrazolyl) thiourea 1 ,3-Dimethyl-5-amino pyrazole (111.0 9.) and benzoyl iso thiocyanate (180.0 9.) were reacted as described in Example IV to give 110.3 9. of the product, mp 221-224 C.
Example XXV N( 1, 3-Dimethyl-5-pyrazolyl)-S-methyl isothiourea hydroiodide (1 ,3-Dimethyl-5-pyrazolyl) thiourea (17.0 g) and 14.2 9 methyl iodide were reacted as described in Example V to give 18.0 9. of the product, mp 158-161 'C.
Analyzed for C7H13lN4S: Theoretical; C = 26.92, H = 4.16, N = 17.94 Found; C = 27.20, H = 4.31, N = 18.07 Example XXVI 2(1, 3-Dimethyl-5-pyrazolyl) amino-2-imidazoline N-(1,3-Dimethyl-5-pyrazolo)-S-methyl isothiourea hydroiodide (18.0 g.) and ethylene diamine (7.0 9.) were reacted as described in Example VI to give.7.60 9. of the product, mp 167-1 69'C.
Analyzed for C8H,3N5: Theoretical; C = 53.63, H = 7.26, N - 39.10 Found; C = 53.58, H = 7.36, N = 39.11 Example XXVII 2(4-Bromo- 1, 3-dimethyl-5-pyrazolyl)-amino-2-imidazoline 2(1,3-Dimethyl-5-pyrazolyl)amino-2-imidazoline (13.25 9.) was treated with 12.89. bromine as described in Example Ill. The product was isolated as the base, 16.159. mp 230-232 C.
Analyzed for C8H,2BrN5: Theoretical; C = 37.21, H = 4.65, N = 27.13 Found; C = 37.35, H = 4.69, N = 26.92 Example XXVIII 2(1, 3-Dimethyl-4-iodo-5-pyrazolyl)-amino-2-imidazoline 2(1 ,3-Dimethyl-5-pyrazolyl) amino-2-imidazoline (8.95 9.) and 13.86 9. iodine was dissolved in 100 ml. acetic acid and stirred 16 hrs. at room temperature. The acetic acid was evaporated and sodium carbonate in water was added. The resulting solid was washed with water, and sodium sulfite solution and then crystallized from methanol to yield 6.85 9. of product, mp 226-227 C.
Analyzed for C8H12lN: Theoretical; C = 31.48, H = 3.93, N = 22.95 Found; C = 31.37, H=3.98, N=23.10 Example XXIX 1-Acetyl-2(1-methyl-5-pyrazolyl) amino-2-imidazoline 5-Amino-1-methyl pyrazole hydrochloride (mp 143-145, from base described in Ber. 98, 3374, 1965) (40.0 g.) and 1-acetyl-2-imidazolinone (43.0 9.) were reacted as described in Example I to give 42.4 9. product mp 158-166 (crystallized from CH3CN) Analyzed for C9H,3N50: Theoretical; C = 52.16, H = 6.32, N = 33.80 Found;C = 52.35, H = 6.46, N = 33.61 Example XXX 2(1 -methyl-5-pyrazolyl) amin o-24midazoline hydrochloride l-Acetyl-2(1-methyl-5-pyrazolyl)amino-2-imidazoline (37.4 9.) was treated with HCI in methanol as described in Example II to give 25.9 9. product mp 204-208 which was converted to the hydrochloride salt mp 187-189.
Analyzed for CgH"N5 HCI: Theoretical; C = 41.69, H = 6.00, N = 34.83 Found; C=41.79, H=6.18, N=34.76 Example XXXI 2(4-Bromo-1-methyl-5-pyrazolyl) amino-2-imidazoline hydrochloride 2(1-Methyl-5-pyrazolyl)amino-2-imidazoline (4.00 g.) was treated with 4.25 g. bromine as described in example VII to give 5.73 g. of product mp 225-228 .
Analyzed for C7H10BrN5.HCl: Theoretical; C = 29.97, H = 3.95, N = 24.96 Found; C=30.13, H=3.99, N=24.62 Example XXXII 2(4-Chloro-1-methyl-5-pyrazolyl) amino-2-imidazoline hydrochloride 2(1-Methyl-5-pyrazolyl) amino-2-imidazoline (15.74 g.) was treated with 2.60 g. chlorine gas in 30 ml. acetic acid, while cooling in ice, by the method of Example VII to give 6.34 9.
mp254-257'.
Analyzed for C7H,0CIN5 HCI: Theoretical; C = 35.61, H = 4.69, N = 29.66 Found; C = 35.79, H = 4.83, N = 29.43.
Example XXXIII 5-Amino-l, 3,4-trimethyl pyrazole hydrochloride 2-Methyl-3-keto-butyronitrile (J. Am. Chem. Soc. 79, 723, 1957) (25.25 g.) in 120 ml.
ethanol was treated with 15 g. methylhydrazine while cooling. The solution was refluxed 3 hours then concentrated in vacuum, benzene added and the solution concentrated agains. Ether was added to give 29.12 g. mp 70-106 of base (contained H20). This was converted to the hydrochloride with HCI in isopropyl alcohol. HCI had mp 286-288.
Analyzed for C6H"N3 HCI: Theoretical; C = 44.59, H = 7.48, N = 26.00 Found; C = 44.40, H = 7.63, N = 25.73 Example XXXIV 1-Acetyl-2(1,3,4-trimethyl-5-pyrazolyl) amino-2-imidazoline 5-Amino-1,3,4-trimethyl pyrazole hydrochloride (8.00 g.) and 1-acetyl-2-imidazolinone (7.05 g.) were reacted as described in Example I to give 7.90 g. mp 212-215 (crystallized from CH3CN) Analyzed for C11H17N5O:Theoretical; C = 56.15, H = 7.28, N = 29.77 Found; C = 55.91, H = 7.19, N = 29.57 Example XXXV 2(1,3,4-Trimethyl-5-pyrazolyl) amino-2-imidazoline 1-Acetyl-2(1,3,4-trimethyl-5-pyrazolyl) amino-2-imidazoline (29.6 9.) was treated with HCI in methanol as described in Example II to give 21.70 9. product (crystallized from CH3CN) Analyzed for CgH15N5: Theoretical; C = 55.93, H = 7.82, N = 36.24 Found; C = 56.24, H=7.95, N=36.16 Example XXXVI 1-Acetyl-2[1-(2-chlorophenyl)-5-pyrazolyl] amino-2-imidazoline 5-Amino-1(2-chlorophenyl) pyrazoie hydrochloride (Farmaco, 22, 68, 1967) (20.5 g.) and 1acetyl-2-imidazolinone (12.6 g.) were reacted as described in Example I to give 17.11 g.
product mp 179-181 (crystallized from CH3CN) Analyzed for C14H14ClN5O: Theoretical; C = 55.36, H = 4.65, N = 23.06 Found; C = 55.96, H = 4.64, N = 23.42 Example XXXVII 2[1-(2-chlorophenyl)-5-pyrazolyl] amino-2-imidazoline 1-Acetyl-2[1-(2-chlorophenyl)-5-pyrazolyl] amino-2-imidazoline (14.0 g.) was treated with HCI in methanol as described in Example II to give 11.10 g. product mp 185-188" (crystallized from CH3CN) Analyzed for C,2H,2CIN5: Theoretical; C = 55.07, N = 4.62, N = 26.76 Found; C = 55.36, H = 4.56, N = 26.92 Example XXXVIII 1 -Acetyl-2( 1, 4-dimethyl-5-pyrazolyl)amino-2-imidazoline 5-amino-i ,4-dimethyl pyrazole hydrochloride (Z.Chem. 388, 1970) (5.72 g.) and 1-acetyl-2- imidazolinone (5.54 g.) were reacted as described in Example I to give 4.723 g. product mp 199-202" (crystallized from CH3CN) Analyzed for C,OH,5N50: Theoretical; C = 54.28, H = 6.83, N = 31.66 Found; C = 54.75, H=6.93, N=31.24 Example XXXIX 2(1, 4-Dimethyl)-5-pyrazolyl) amino-2-imidazoline 1-Acetyl-2(1 ,4-dimethyl-5-pyrazolyl) amino-2-imidazoline (4.72 g.) was treated with HCI in methanol as described in Example II to give 3.348 g. product mp 200-202" (crystallized from CH3CN) Analyzed for C8H,3N5:Theoretical; C = 53.63, H = 7.26, N = 39.10 Found; C = 54.00, H = 7.62, N = 39.20 Example XL 1-Acetyl-2(3-methyl-1-phenyl-5-pyrazolyl) amino-2-imidazoline 5-Amino-3-methyl- 1 -phenyl pyrazole hydrochloride (37.8 g.) and - 1 -acetyl-2-imidazoline (27.4 g.) were reacted as described in Example I to give 35.4 g. product. mp 153-162" (crystallized from CH3CN) Example XLI 2(3-Methyl-1-phenyl-5-pyrazolyl)amino-2-imidazoline hydrochloride 1-Acetyl-2-(3-methyl-1-phenyl-5-pyrazolyl) amino-2-imidazoline (35.0 g.) was treacted with HCI in methanol as described in Example II to give 28.7 g. product as the hydrochloride. mp 182-184 Analyzed for C13H15N5,HCl: Theoretical; C = 56.22, H = 5.81;N = 25.21 Found; C = 56.24, H = 5.83, N = 25.08 Example XLII 2(3-Ethyl- 1-methyl-5-pyrazolyl) amino-2-imidazoline hydrochloride 5-Amino-3-ethyl-1 -methyl pyrazole (British Patent 863,060) (35.2 g.) and 1 -acetyl-2-imidazoli- none (43.2 g.) were reacted as described in Example I to give 1-acetyl -2-(3-ethyl-1-methyl-5pyrazolyl) amino-2-imidazoline which was de-acetylated without purification by the method of Example II giving 39.3 g. product. mp 160-162" Analyzed for CgH15N5 HCI: Theoretical;C = 47.06, H = 7.02, N = 30.49 Found; C = 46.89, H = 7.01, N = 30.29 Example XLIII 5-Amino- 1 -(4-fluorophenyl)-3-methyl-pyrazole 4-Fluorophenylhydrazine HCI (60.0 g.) 175 ml. water, 70 ml. concentrated hydrochloric acid and 28.8 g. 3-amino-2-butene nitrile were refluxed one hour. The solution was cooled and made basic with concentrated ammonia. The solid was filtered and crystallized from ether to get 51.05 g. product, mp 108-110 , which was converted to the HCI salt mp 227-229 Analyzed for C10H,OFN3 HCI: Theoretical; C = 52.76, H = 4.87, N = 18.47 Found; C = 52.96, H = 4.87, N = 18.36 Example XLIV 1-Acetyl-2[1-(4-fluorophenyl)-3-methyl-5-pyrazolyl] amino-2-imidazoline 5-Amino-1-(4-fluorophenyl)-3-methylpyrazole (25 g.) and 1 -acetyl-2-imidazolinone (20.2 g.) were reacted as described in Example I to give 21.97 g. product, mp 189-191 Analyzed for C15H'6FNsO: Theoretical;C = 59.79, H = 5.31, N = 23.24 Found; C = 59.96, H = 5.42, N = 23.66 Example XLV 2[1-(4-Fluorophenyl)-3-methyl-5-pyrazolyl] amino-2-imidazoline l-Acetyl-2C1 -(4-fluorophenyl)-3-methyl-5-pyrazolyll amino-2-imidazoline (21.0 9.) was treated with HCI in methanol as described in Example II to give 7.503 9. mp 213-215 Analyzed for C13H'4FN5: Theoretical; C = 60.22, H = 5.44, N = 27.01 Found; C = 59.94, H = 5.54, N = 26.98 Example XLVI 5-Amino-l -(4-fluorophenyl)-pyrazole hydrochloride 4-Fluorophenylhydrazine was converted to this product by the method described in Farmaco 22, 68, 1967. mp of HCI salt, 201-210 Analyzed for C9H8FN3.HCl:Theoretical; C = 50.60, H = 4.24, N = 19.67 Found; C = 50.56, H = 4.25, N = 19.75 Example XLVII 1-Acetyl-2[1-(4-fluorophenyl)-5-pyrazolyl]amino-2-imidazoline 5-Amino-1-(4-fluorophenyl)pyrazole HCI (21 9.) and 1-acetyl-2-imidazolinone (15.4 9.) were reacted as described in Example I to give 20.76 9. product. mp.162-164 Analyzed for C14H14FN5O: Theoretical; C = 58.53, H = 4.91, N = 24.37 Found; C=58.61, H=4.98, N=24.75 Example XL VIII 2[1-(4-fluorophenyl)-5-pyrazolyl] amino-2-imidazoline 1-Acetyl-2[1-(4-fluorophenyl)-5-pyrazolyl] amino-2-imidazoline (17.13 9.) was treated with HCI in methanol as described in Example II to give 12.06 9. product. mp 195-197 Analyzed for C12H12FN5:Theoretical; C = 58.77, H = 4.93, N = 28.55 Found; C = 58.74, H = 4.98, N = 28.60 Example XLIX 1-Benzoyl-2-(1,3-dimethyl-5-pyrazolyl) amino-2-imidazoline 5-amino-1 ,3-dimethylpyrazole (20.0 9.) and 1-benzoyl-2-imidazolinone (British patent 1,392,849) (28.4 9) were reacted as described in Example I to give 22.02 9. product. mp 147-149 Analyzed for C15H17N50: Theoretical; C = 63.58, H = 6.05, N = 24.72 Found; C = 63.51, H = 6.06, N = 24.65 Example L 5-Amino-1(3-trifluoromethylphenyl)-3-methylpyrazole hydrochloride 3-Trifluoromethylphenyl hydrazine (Tetrahedron, 1960, 69) (25.0 9.) was reacted with 3amino-2-butene nitrile (12.7 9.) as described in Example XLIII to give 36.1 9. product as HCI salt, mp 222-226 .
Analyzed for C11H10F3N3.HCl: Theoretical; C=47.58, H = 3.99, N = 15.13 Found; C = 47.88, H = 4.13, N = 14.78 Example LI 1-Acetyl-2[1-(3-trifluoromethylphenyl)-3-methyl-5-pyrazolyl]amino-2-imidazoline 5-Amino-1-(3-trifluoromethylphenyl)-3-methyl pyrazole HCI (20.0 9.) and 1-acetyl-3-imidazolinone (11.1 9.) were reacted as described in Example I to give 15.0 9. product. mp 173-175 Analyzed for C,6H,6F3N50: Theoretical;C = 54.70, H = 4.59, N = 19.93 Found; 0=54.77, H=4.66, N = 19.93 Example LII 2[1-(3-Trifluoromethylphenyl)-3-methyl-5-pyrazolyl] amino-2-imidazoline hydrochloride 1 -Acetyl-2[ 1 -(3-Trifluoromethylphenyl)-3-methyl-5-pyrazolylj amino-2-imidazoline (13.0 9.) was treated with HCI in methanol as described in Example II to give 10.12 9. of product as the HCI salt, mp 205-206 .
Analyzed for C14H14F3N5.HCl: Theoretical; C = 48.63, H = 4.37, N = 20.25 Found; C = 48.45, H = 4.48, N = 20.08 Example LIII 5-Amino-1-(3-Trifluoromethylphenyl) pyrazole 3-Trifluoromethylphenyl hydrazine was converted to this product by the method described in Farmaco 22 68, 1967, mp 77-79 Analyzed for C,0H6FSN3: Theoretical; C = 52.87, H = 3.55, N = 18.49 Found; C = 53.13, H = 3.54, N = 18.67 Example LIV 1-Acetyl-2[1-(3-Trifluoromethylphenyl)-5-pyrazolyl] amino-2-imidazoline 5-Amino-1-(3-trifluoromethylphenyl) pyrazole (19.0 g.) and 1-acetyl-2-imidazolinone (12.9 g.) were reacted as described in Example I to give 16.85 g. product, mp 194-197 .
Analyzed for C,5H,4F3N50: Theoretical; C = 53.41, H = 4.18, N = 20.76 Found; C = 53.31, H = 4.27, N = 20.56 Example LV 2-[1-(3-Trifluoromethylphenyl)-5-pyrazolyl] amino-2-imidazoline hydrochloride 1-Acetyl-2-[1-(3-Trifluoromethylphenyl)-5-pyrazolyl] amino-2-imidazoline (14.5 g.) was treated with HCl in methanol as described in Example II to give 10.69 g. product as the HCl salt, mp 151-153'.
Analyzed for C13H12F3N3HCl: Theoretical; C = 47.07, H = 3.95, N = 21.11 Found; C = 47.39, H = 4.04, N = 20.93 Example LVI 5-Amino-3-methyl-1-(1-naphthyl) pyrazole hydrochloride 1-Naphthyl hydrazine HCI (25.0 9.) was reacted with 3-amino-2-butene nutrile (10.6 9.) as described in Example XLIII to give 26.55 g. product as the HCI salt (crystallized from CH3CN and ether) mp 210-213 .
Analyzed for C,4H13N3HCI: Theoretical; C = 64.74, H = 5.43, N = 16.18 Found; C = 64.45, H = 5.31 N = 16.10 Example LVII 1 -Acetyl-2 1 -(1 -naphthyl)-3-methyl-5-pyrazolyl] amino-2-imidazoline 5-Amino-3-methyl-1-(1-naphthyl) pyrazole HCI (20.0 g.) and 1-acetyl-2-imidazolinine (12.0 g.) were reacted as described in Example I to give 19.80 g. product, mp 194-195 Analyzed for C19H19N5O: Theoretical; C = 68.45, H = 5.74, N = 21.01 Found; C = 68.35; H = 5.81, N = 21.29 Example LVIII 2[1-(l-Naphthyl)-3-methyl-5-pyrazolyl] amino-2-imidazoline 1-Acetyl-2[1-(1-naphthyl)-3-methyl-5-pyrazolyl] amino-2-imidazoline (15.27 g.) was treated with HCI in methanol as described in Example II to give 11.82 g. product, mp 221-224 .
Analyzed for C,7H17N5: Theoretical, C = 70.08, H = 5.88, N = 24.04 Found, C = 70.02, H = 5.91, N = 24.27 Example LVIX 5-Amino-3-methyl-1-(4-chloro-2-methylphenyl) pyrazole 5-chloro-2-methylphenylhydrazine HCI (80.32 9.) was reacted with 3-amino-2-butene nitrile (32.5 g.) as described in Example XLIII to give 60.5 g. product, mp 86-87 .
Analyzed for C11H12ClN3: Theoretical; C = 59.59, H = 5.45, N = 18.95 Found; C = 59.44, H = 5.49, N = 18.73.
Example LX 1 cetyl-2[ 1 (4-chloro-2-methylphenyl)-3-methyl-5-pyrazolyl] amino-2-imidazoline 5-Amino-3-methyl-1 -(4-chloro-2-methylphenyl) pyrazole (22.16 g.) and 1 -acetyl-2-imidazoli- none (15.4 9.) were reacted as described in Example I to give 13.1 g. of product, mp 1 95- 1 95 Analyzed for C,6H,8CIN50: Theoretical; C = 57.91, H = 5.96, N = 21.10 Found; 0=57.87, H = 5.52, N = 21.14 Example LXI 2-[1(4-chloro-2-methylphenyl)-3-methyl-5-pyrazolyq amino-2-imidazoline HCI 1-Acetyl-2[1-(4-chloro-2-methylphenyl)-3-methyl-5-pyrazolyl] amino-2-imidizoline (10.0 g.) was treated with HCI in methanol as described in Example II to give 7.4 g. product as the HCI salt, mp 134-135 .
Analyzed for C,4H,6CIN5 HCI: Theoretical; C = 51.54, H = 5.25, N = 21.47 Found; C = 51.70, H = 5.18, N = 21.56 Example LXII 1-Acetyl-2(1-methyl-3-phenyl-5-pyrazolyl) amino-2-imidazoline 5-Amino-1-methyl-3-phenylpyrazole (17.3 g.) and 1-acetyl-2-imidazolinone (15.4 g.) were reacted as described in Example I to give 14.0 g. product, mp 154-155 Analyzed for C,5H,7N50: Theoretical; C = 63.58, H = 6.04, N = 24.71 Found; C = 63.79, H = 6.22, N = 24.95 Example LXIII 2(1-Methyl-3-phenyl-5-pyrazolyl)-amino-2-imidazoline hydrochloride 1-Acetyl-2-(1-methyl-3-pyhenyl-5-pyrazolyl)amino-2-imidazoline (10.0 g.) was treated with HCl in methanol as described in Example II to give 5.5 g. of product as the HCl salt, mp 195-197 .
Analyzed for C13H15N5.HCl: Theoretical; C = 56.21, H = 5.80, N = 25.21 Found; 0=56.01, H = 5.85, N = 25.24 Example LXIV 1-Acetyl-2[1-(4-methoxyphenyl)-3-methyl-5-pyrazolyq amino-2-imidazoline 5-Amino-3-methyl-1-(4-methoxyphenyl) pyrazole HCI (Farmaco 17. 443, 1962) (23.9 g.) and 1-acetyl-2-imidazolinone (15.49.) were reacted as described in Example I to give 14.5 g. of product, mp 129-131'.
Analyzed for C16H19N5O2: Theoretical; C = 61.32, H = 6.11, N = 22.34 Found; C = 60.87, H=6.15, N = 22.05 Example LXV 2-[1-(4-Methoxyphenyl)-3-methyl-5-pyrazolyl]amino-2-imidazoline HCl 1-Acetyl-2[1-(4-methoxyphenyl)-3-methyl-5-pyrazolyl] amino-2-imidazoline (1 3.1 9.) was treated with HCI in methanol as described in Example II to give 7.9 g. of product as the HCI salt, mp 197-198 .
Analyzed for C14H17N5O.HCl: Theoretical; C = 54.63, H = 5.89, N = 22.75 Found; C= 54.77, H = 5.97, N = 22.91 Example LXVI 1 -Acetyl-2- 1 -(3-chlorophenyl)-3-methyl-S-pyrazolylj amine-2-imidazoline 5-Amino-3-methyl-1-(3-chlorophenyl)pyrazole (Farmaco, 19, 638, 1964) (31.14 g.) and 1acetyl-2-imidazolinone (23.06 g.) were reacted as described in Example I to give 25.1 g.
product, mp 140-141 .
Analyzed for C15H16ClN5O: Theoretical; C = 56.69, H = 5.07, N = 22.03 Found; C=56.53, H=5.12, N=22.13 Example LXVII 2-[1-(3-chlorophenyl)-3-methyl-5-pyrazolyl]amino-2-imidazoline HCl 1-Acetyl-2-[1-(3-chlorophenyl)-3-methyl-5-pyrazolyl] amino-2-imidazoline (19.7 g.) was treated with HCl in methanol as described in Example II to give 6.5 g. product as the HCl salt, mp 208-209'.
Analyzed for C,3H,4CIN5 HCI: Theoretical; C = 50.01, H = 4.84, N = 22.43 Found; C = 50.43, H = 4.76, N = 22.39 Example LXVIII 1 -Acetyl-2f 1 -(2-methyiphenyl)-3-m ethyl-5-pyrazolyl]amin o-2-imidazoline 5-Amino-3-methyl-1-(2-methylphenyl)pyrazole HCI (Farmaco, 19, 638, 1964) (26.5 9.) and 1acetyl-2-imidazolinone (18.2 g.) were reacted as described in Example I to give 12.6 g. product, mp 160-161 .
Analyzed for C16H19N5O: Theoretical; C = 64.62, H = 6.44, n = 23.55 Found; C = 64.14, H = 6.27, N = 23.57 Example LXIX 2[1-(2-Methylphenyl)-3-methyl-5-pyrazolyl] amino-2-imidazoline 1-Acetyl-2-[1-(2-methylpenyl)-3-methyl-5-pyrazolyl] amino-2-imidazoline (7.0 g.) was treated with HCI in methanol as described in Example II to give 4.6 g. of product, mp 168-169 .
Analyzed for C14H17N5: Theoretical; C = 65.85, H = 6.71, N = 27.42 Found; C = 65.73, H = 6.78, N = 27.77 Example LXX 5-Amino-3-methyl- 1(3, 4-dichlorophenyl) pyrazole 3,4-Dichlorophenyl hydrazine HCI (50.0 9.) was reacted with 3-amino-2-butene nitrile (18.31 g.) as described in Example XLIII to give 18.7 g. product, mp 110-112'.
Analyzed for CaoHgCI2N3; Theoretical; C = 49.61, H = 3.74, N = 17.35 Found; C = 50.09, H=3.75, N=17.43 Example LXXI 1-Acetyl-2[1-(3,4-dichlorophenyl)-3-methyl-5-pyrazolyq amino-2-imidazoline 5-Amino-3-methyl-1-(3,4-dichlorophenyla) pyrazole (16.6 9.) and 1 -acetyl-2-imidazolinone (10.6 9.) were reacted as described in Example I to give 8.5 9. of product, mp 156-157 .
Analyzed for C,5H,5CI2N50: Theoretical; C = 51.15, H = 4.29, N = 19.88 Found; C=51.16, H=4.37, N = 19.82 Example LXXII 2[1-3, 4-dichlorophenyl)-3-methyl-5-pyrazolyl] amino-2-imidazoline HCI 1-Acetyl-2[1 ,-(3,4-dichlorophenyl)-3-methyl-5-pyrazolyl] amino-2-imidazoline (7.0 g.) was treated with HCI in methanol as described in Example II to give 2.7 g. of product as the HCI salt, mp 266-267 .
Analyzed for C,3H,3CI2N5 HCI: Theoretical; C = 40.04, H = 4.07, N = 20.20 Found; C = 45.32, H=4.18, N = 20.42 Example LXXIII 1-Acetyl-2-(1-benzyl-3-methyl-5-pyrazolyl) amino-2-imidazoline 5-Amino-1-benzyl-3-methylpyrazole (J. Gen. Chem. USSR, 31, 2307, 1961) (17.09.) and and 1acetyl-3-imidazolinone (14.0 9.) were reacted as described in Example I to give 11.7 9. of product, mp 148-149 .
Analyzed for C18H19N5O: Theoretical; C = 64.63, H = 6.44, N = 23.55 Found; C = 64.83, H = 6.55, N = 23.82 Example LXXIV 2(1-Benzyl-3-methyl-5-pyrazolyl)amino-2-imidazoline HCI 1-Acetyl-2-(1-benzyl-3-methyl-5-pyrazolyl) amino-2-imidazoline (12.5 9.) was treated with HCI in methanol as described in Example II to give 7.2 9. of product, mp 198-199 , (as the HCI salt).
Analyzed for C,4H,7N5 HCI: Theoretical; C = 57.63, H = 6.22, N = 24.00 Found; C = 57.76, H = 6.33, N = 24.03 Example LXXV 2-[1-(4-Hydroxyhphenyl)-3-methyl-5-pyrazolyl] amino-2-imidazoline hydrochloride 2-[ 1 -(4-methoxyphenyl)-3-methyl-5-pyrazolyl]amino-2-imidazoline hydrochloride (3.0 9.) was refluxed with 75 ml. 48% HBr for 16 hours. Addition of ammonia gave a solid which was converted to the hydrochloride with concentrated HCl giving 1.50 9. product mp 286-287 .
Analyzed for C,3H,5N50 HCI: Theoretical; C = 53.1 5, H = 4.59, N = 23.84 Found; C = 52.72, H = 5.62, N = 23.67 By methods described in the proceeding examples, the following compounds were synthesized: a) 2-(1-benzyl-5-pyrazolyl) amino-2-imidazoline HCI, mp 141-143 .
b) [1 -(3-nitrophenyl)-3-methyl-5-pyrazolyl] amino-2-imidazoline HCI, mp 218-220 .
c) 2-(3,4-dimethyl-1-phenylpyrazolyl) amino-2-imidazoline HCI, mp 209-210 .
d) 2(1 ,4-Diphenyl-3-methylpyrazolyl) amino-2-imidazoline HCI, mp 252-254 .
e) 2(1 ,3-dimethyl-4-phenylpyrazolyl) amino-2-imidazoline HCI, mp 249-251 .
f) 2[1-(2-biphenylyl)-3-methylpyrazolyl] amino-2-imidazoline, mp 204-205 .
9) 2[3-methyl-1 -(3-quinolinyl) pyrazolyl] amino-2-imidazoline, mp 1 90-1 92'.
Example LXXVI 1 -Methyl-2( 1, 3-dimethyl-5-pyrazolyl) amino-2-imidazoline N(1,3-Dimethyl-5-pyrazolyl)-5-methyl isothiourea hydroiodide (Example XXV) (20.0 9) and 11.5 9. N-methyl ethylenediamine were heated to 120 for 30 minutes and to 160 for 1 hour.
After cooling, methylene chloride was added and the solid which formed was filtered and discarded. The methylene chloride solution was shaken with 15% KOH solution, dried over potassium carbonate, concentrated and the residue crystallized from acetonitrile to get 1 0.1 6 9.
product, mp. 128-130 .
Analyzed for CgH15N5: Theoretical; C = 55.93, H = 7.82, N = 36.24 Found; C = 55.78, H = 7.95, N = 36.05 The anti-inflammatory activity of the compounds of this invention was established using the reverse passive Arthus reaction in the rat as described by G. W. Carter and R. A. Krause in Federation Proceedings, Vol. 35, p. 774, 1976. The carrageenin rat paw edema test (Winter et.
al, Proc. Soc. Exp. Biol. Med., 111, 554, 1962) can be used to establish anti-inflammatory activity, however, unlike carrageenin induced edema, the Arthus reaction is a well characterized immune reaction which bears close resemblance to the pathogenisis of rheumatoid arthritis.
The Arthus reaction represents one of the oldest and best studied models of immunological injury. It is produced by the injection of antigen locally into a hyperimmunized animal or by the injection of a small amount of antibody into the skin of an animal that has just previously been given a large amount of soluble antigen intravenously. In both cases the antigen and antibody become deposited in the walls of small venules. Plasma complement is rapidly bound and activated. Within a few hours neutrophils (PMNs) accumulate resulting in disruption of the basement membrane of vessel walls and marked edema and hemorrage in the surrounding tissue.
Although, the etiology of Rheumatoid arthritis remains obscure, it is almost certain that immunological mechanisms play an important role in the pathogenesis of this disease.
Therefore, inflammation induced by immunological reactions, which are believed to be important in the inflammatory processes of rheumatoid arthritis, make particularly desirable tools for the screening of potential anti-inflammatory agents. The usefulness of such a model depends upon how closely it represents the underlying pathological mechanisms of rheumatoid arthritis.
Based upon currently available evidence, a plausible sequence of events leading to the joint leisions in rheumatoid arthritis can be constructed. An initiating antigen, perhaps a transient synovial infection, results in an immune response and retention of the antigen within the joint structure. The interaction of antigen with developing antibodies results in the deposition of immune complexes. These complexes may fix and activate complement, causing the generation of a number of phlogistic and chemotactic substances. Phagocytosis of the complexes by attracted polymorphonuclear leukocytes (PMNs) leads to the release of lysosomal constituents.
The enzymes released from lysosomes can erode articular cartilage and produce inflammation in the joint. The striking resemblance of these events to the Arthus phenomenon point to the utility of the arthus reaction as a screen for anti-inflammatory compounds.
The reverse passive Arthus reaction test in rats is conducted as follows. Male Sprague-Dawley rats weighing approximately 130-160 g. are used, 4 rats per group. All animals are injected intravenously with 0.5 ml. 0.075% Bovine Serum Albumin (B.S.A.) + 0.2% Evans Blue solution. Each rat then receives an oral dose of drug; one drug is administered per group.
Thirty minutes subsequent to drug dosing, each animal is injected intradermally with .05 ml.
1.44% Anti-B.S.A. into the dorsal skin. Four hours later the animals are sacrificed, the dorsal skin reflexed, and the lesion excised. Two perpendicular diameters of each lesion are measured.
The average diameters of the lesions from the treated groups are compared with the average diameters from the control group to determine any drug effect.
The anti-inflammatory activity of representative compounds of this invention, as determined by the reverse passive Arthus reaction test in rats, is summarized in Table I.
TABLE I Anti-lnflammatory Effect of Compounds of Formula A in the Reverse Passive Arthus Reaction Test in Rats
Percent Inhibition of Arthus R1 R2 R3 R4 Reaction (oral dose mg/kg) Me2CH Me Br H 20% (100 mg/kg) Me2CH Me H H 20% (50 mg) 29% (100 mg) Me2CHCH2-CH2 Me Br H 16% (100 mg) H H Br H 15%(100mug) Me Me2CH Br H 37% (50 mg) 42% (100 mg) Me2CH-CH2-CH2 Me H H 15% (100 mg) Me Me2CH H H 33%(50 mg)42%(100 mg) H H H H (100 mug) Me2CH Me2CH Br H 27% (100 mg) Me2CH Me2CH H H 11% (100 mg) C6H5 H Br H 41% (25 mg) 59% (100 mg) C6H5 H H H 62% 25 mg) 75% (100 mg) C8H5 CeH5 Br H 17% (100 mg) QH5 C6H5 H H 32% (100mg) Me Me I H 43%(100mug) Me Me Br H 45% (50 mg) Me Me H H 55%(100mug) C6H5 H H COCH3 70% (100 mg) Me2CH Me H COCH3 30% (50 mg) 39% (100 mg) Me Me2CH H COCH3 18% (100 mg) Me Me (5) CI COCH3 39% (25 mg) 63% (100 mg) Me Me (5)(CI) H 49% (10 mg) 64% (25 mg) 69% (100 mg) Note: Me represents CH3. The R3 substituent is located in the 4 position unless otherwise noted.
The antihypertensive activity of the compounds of this invention was established in genetically hypertensive (SH) rats. In this test, adult male SH rats of the Okamoto strain were trained to be restrained in a wire mesh cylinder for measurement of blood pressure. One half hour prior to blood pressure measurement, the rats were placed in a warm chamber maintained at a constant temperature of 36"C. An occluding cuff, attached to a programmed sphygmomanometer, was placed near the base of the tail of each rat and the pressure in the cuff was increased automatically from 0 to 250 mm Hg at a rate of 10 mm Hg per second. The cuff was then deflated at the same rate. The total time required for each cycle of inflation and deflation of the cuff was 50 seconds and the interval between successive cycles was one minute.A photocell was placed distal to the cuff to sense the arterial pulse wave. As the pressure in the cuff increased, the pulse wave completely disappeared when the cuff pressure just exceeded the systolic arterial blood pressure. During deflation, the pulse wave reappeared at approximately the same pressure. Five interference-free signals obtained during deflation were recorded for each rat. Only those rats with a systolic blood pressure of 1 80 mm Hg or more during the control period were used in this study. A model 7 Grass polygraph was used to record the cuff pressure and the arterial pulse wave. The heart rate of the rat was computed from the record of the arterial pulse wave. The compounds tested were administered orally to the rats, the results recorded below in Table II. From Table II it can be seen that the compounds exhibited significant antihypertensive activity.
TABLE II Antihypertensive Effect, Lowering in Blood Pressure Compound Dose, Time, % Decrease R1 R2 R3 R4 mg. hr. in b.p.
1. CH3 H H H 10 1 19 3 6 10 2. CH3 H CH3 H 30 4 44 3. CH3 H Br H 30 4 19 4. CH3 H C6H5- H 30 4 37 5. CH3 CH3 H H 1 1 21 0.3 1 11 6. CH3 CH3 Br H 0.3 6 13 7. CH3 CH3 I H 10 6 49 8. C6Hs- C6H5- H H 100 4 12 9. C6H5- C6H5- Br H 100 4 18 10. C6H5- H H H 10 6 20 11. (CH3)2CH- (CH3)2CH- H H 100 4 12 12. C6H5 H Br H 30 4 42 13. (CH3)2CH- (CH3)2CH- Br H 10 24 17 14. CH3 (CH3)2CH- H H 30 4 26 15. CH3 (CH3)2CH Br H 100 4 37 16. (CH3)2CH- CH3 H H 30 6 15 17. (CH3)2CH- CH3 Br H 100 4 12 18. C6H5 H H COCH3 30 4 38 19. CH3 (CH3)2CH- H COCH3 100 4 17 20. (CH3)2CH CH3 H COCH3 100 4 13 21. CH3 H H COCH3 100 4 16 22. CH3 CH3 CH3 COCH3 10 6 14 23. CH3 CH3 H COCH3 30 4 19 The diuretic and saluretic activity of the compounds of this invention was established in genetically hypertensive (SH) rats.In this test, male genetically hypertensive (SH) rats, weighing 250-350 grams, were used. The rats were loaded with 0.9% sodium chloride solution, the volume of the load being five percent of their body weight. At the same time, the rats were dosed with the drugs to be tested and placed individually in stainless steel metabolism cages.
No food or water was given to the animals during the test. Urine was collected at hourly intervals during the first eight hours and at the 24-hour interval folowing drug administration.
The volume of excreted urine was accurately measured at each time interval. Pooled urine samples at time intervals of 2, 8 and 24 hours were analyzed for sodium, potassium and chloride ions and for uric acid. Sodium and potassium were estimated using a Digital Readout Flame Photometer (Instrumentation Labs.). Chloride was estimated by the method of Schales and Schales (J. Biol. Chem., 140:879, 1941). Uric acid was determined by a colorimetricuricase method adapted according to an American Monitor Corporation procedure using Beckman's DSA-560 colorimeter.
The compounds were orally administered in various comparable doses. Each dose was tested in eight rats. Controls received vehicle (0.5% methylcellulose), orally administered in the same volume of 2 ml./kg. Statistical analysis of the data was done by student's t-test.
The results of the tests are recorded below in Tables Ill and IV.
TABLE III Compound 5 - 30 mg/kg PO Saline Load 56 M NTR VOLUME SODIUM POTASSIUM CHLORIDE URIC ACID OSMOLALITY NA/K 2 HOUR (ML/KG) (MEG/KG) (MEQ/KG) (MEQ/KG) (MG/KG) (MOSM/KG) PATIO CONTROL 7.6116 1.3100 0.9362 1.7079 0.8465 7.5816 1.4189 DRUG 44.4578 5.2650 1.2560 5.7868 0.9468 15.6478 4.2497 DELTA 36.8462 3.9550 0.3199 4.0789 0.1004 8.0662 2.8309 T-CALC 8.7398 6.9379 2.5959 6.8866 0.9376 5.4916 5.5492 PRO2 0.0000* 0.0000* 0.0211* 0.0000* 0.3644 0.0001* 0.0001* 6 HOUR CONTROL 27.1901 3.6659 2.0283 4.4942 2.3564 19.0081 1.8810 DRUG 53.0724 6.78i4 2.0426 7.8450 2.0423 22.8533 3.5898 DELTA 25.8823 3.1193 0.0142 3.3508 -0.3141 3.8452 1.7088 T-CALC 6.4744 7.8305 0.0536 8.2805 -1.2999 1.4939 3.4520 PROB 0.0000* 0.0000* 0.9580 0.0000* 0.2146 0.1574 0.0039* 24 HOUR CONTROL 67.6368 8.2250 4.1340 9.0452 7.6219 43.5752 2.0283 DRUG 67.9638 9.0141 3.7650 9.7495 8.0406 43.7743 2.4400 DELTA 0.3270 0.7891 -0.3690 0.7043 0.4188 0.1991 0.4117 T-CALC 0.0985 2.1742 -1.1207 1.6432 0.7765 0.0772 2.3090 PROB 0.9307 0.0473* 0.2813 0.1226 0.4504 0.9395 0.0367* Compound 5 - 10 mg/kg PO Saline Load 5% M NTR VOLUME SODIUM POTASSIUM CHLORIDE URIC ACID OSMOLALITY NA/K 2 HOUR (ML/KG) (MEQ/KG) (MEQ/KG) (MEQ/KG) (MG/KG) (MOSM/KG) RATIO CONTROL 7.6116 1.3100 0.9362 1.7079 0.8465 7.5816 1.4189 DRUG 21.021:: 2.8179 1.1273 3.2917 0.7787 10.2919 2.3621 DELTA 13.4098 1.5079 0.1911 1.5837 -0.0678 2.7103 0.9432 T-CALC 2.7641 2.4505 0.9375 2.2189 -0.5258 1.3702 3.5506 PROB 0.0152* 0.0280* 0.3644 0.0435* 0.6072 0.1938 0.0032* 6 HOUR CONTROL 27.1901 3.6659 2.0283 4.4942 2.3564 19.0081 1.8810 DRUG 33.2111 5.1149 2.2309 5.9350 2.3069 21.2437 2.3173 DELTA 6.0210 1.4490 0.2026 1.4408 -0.0495 2.2356 0.4363 T-CALO 1.1995 3.0244 0.8293 2.9169 -0.1979 0.8593 1.8664 PROS 0.2503 0.0091* 0.4209 0.0113* 0.8460 0.4046 0.0831 24 HOUR CONTROL 67.6368 8.2250 4.1340 9.0452 7.6219 43.5752 2.0283 DRUG 61.6883 8.2715 4.1756 9.1398 8.1716 45.4269 2.0164 DELTA -5.9485 0.0465 0.0416 0.0946 0.5498 1.8517 -0.0119 T-CALC -1.5607 0.1434 0.1266 0.3088 0.8797 0.7126 -0.0789 PROB 0.1409 0.8880 0.9010 0.7620 0.3939 0.4878 0.9382 Compound 5 - 3 n;,'kg PO Saline Load 5% M NTR VOLUME SODIUM POTASSIUM CHLORIDE URIC ACID OSMOlAtITY NA/K 2 HOUR (ML/KG) (MEQ/KG) (MEQ/KG) (MEQ/KG) (MG/KG) $MOSM/KG) PATIO CONTROL 7.6116 1.3100 0.9362 1.7079 0.8465 7.5816 1.4189 DRUG 11.2864 1.5989 0.8779 1.9609 0.6676 7.1801 1.7689 DELTA 3.6748 0.2889 -0.0583 0.2530 -0.1789 -0.4016 0.3501 T-CALC i.2720 0.7785 -0.3127 0.5196 -1.3703 -0.2637 1.7398 PROSB 0.2241 0.4492 0.7591 0.6115 0.1922 0.7962 0.1055 6 HOUR CONTROL 27.i901 3.6659 2.0283 4.4942 2.3564 19.0081 1.8810 DRUG 32.5374 4.0183 1.9649 Ç.7812 2.2186 18.5279 2.0750 DELTA 5.3473 0.3524 -0.0634 0.2870 -0.1378 -0.4802 0.1941 T-CALC 1.1183 1.0269 -0.2945 0.8052 -0.7450 -0.1991 0.8736 PROB 0.2823 0.3219 0.7727 0.4342 0.4686 0.8450 0.3971 24 HOUR CONTROL 67.6368 8.2250 4.1340 9.0452 7.6219 43.5752 2.0283 DRUG 72.2726 8.6323 3.8381 9.2950 7.8404 44.7048 2.2,20 DELTA 4.6358 0.4072 -0.2959 0.2498 0.2186 1.1296 0.2437 T-CALC 1.10'1 1.0828 -0.9694 0.6463 0.3615 0.4412 1.6835 PROB 0.2869 0.2972 0.3488 0.5286 0.7232 0.6658 0.1144 Compound 4 - 1 mg/kg PO Saline Load 5% M NTR VOLUME SODIUM POTASSIUM CHLORIDE URIC ACID OSMOLALITY NA/K 2 HOUR (ML/KG) (MEQ/KG) (MEQ/KG) (MEQ/KG) (MOSM/KG) RATIO CONTROL 7.6116 1.3100 0.9362 1.7079 7.5816 1.4180 DRUG 7.0773 1.2235 0.9145 1.6047 6.6432 1.3387 DELTA -0.5344 -0.0865 -0.0217 -0.1032 -0.9385 -0.0802 T-CALC -0.2845 -0.2759 -0.1027 -0.2461 -0.7789 -9.6277 -0.5344 PROB 0.7802 0.7866 0.9197 0.8092 0.4490 0.5411 0.6021 6 HOUR CONTROL 27.1901 3.6659 2.0283 4.4942 2.3564 19.0081 1.88i0 DRUG 27.6841 4.0157 2.2703 4.7160 2.3009 19.4662 1.7987 DELTA 0.4940 0.3499 0.2420 0.2218 -0.0555 0.4581 -0.0822 T-CALC 0.1340 0.9616 0.8815 0.5283 -0.2794 0.1785 -0.5116 PROB 0.8953 0.3525 0.3929 0.6055 0.7840 0.8609 0.6169 24 HOUR CONTROL 67.6368 8.2250 4.1340 9.0452 7.6219 43.5752 2.0283 DRUG 71.0572 8.7267 4.2677 9.2000 7.7852 45.7412 2.0826 DELTA 3.4204 0.5016 0.1337 0.1548 0.1634 2.1660 0.0543 T-CALC 0.7828 1.6449 0.3990 0.4666 0.2624 0.8335 0.355S PROB 0.4468 0.1222 0.6959 0.6480 0.7968 0.4185 0.7273 TABLE IV DOSE VOLUME SODIUM CULORIDE COMPOUND MG/KG ROUTE SPECIES LOAD TIME (ML/KG) (MEQ/KG) (MEQ/KG) 5 30 PO 8 M NTR SAL 5% 0-2 2.20/.00* 1.29/.20 1.26/.28 0-6 1.67/.00* 0.94/.54 0.94/.61 2-6 1.12/.54 0.67/.03* 0.71/.07 5 10 PO 8 M NTR SAL 5% 0-2 1.78/.01* 1.71/.01* 1.53/.02* 0-6 1.13/.26 1.11/.32 1.05/.51 2-6 0.56/.01* 0.65/.07 0.66/.03* 8 100 PO 8 M NTR SAL 5% 0-2 0.30/.00* 0.29/.00* 0.30/.00* 0-6 0.53/.00* 0.54/.00* 0.57/.00* 2-6 0.74/.12 0.72/.03* 0.76/.05* 8 100 PO 8 M NTR SAL 5% 0-2 0.31/.00* 0.27/.00* 0.35/.00* 0-6 0.43/.00* 0.38/.00* 0.49/.00* 2-6 0.53/.01* 0.45/.00* 0.50/.00* 8 30 PO 8 M NTR SAL 5% 0-2 0.95/.88 0.79/.31 0.80/.33 0-6 1.05/.82 0.80/.06 0.85/.18 2-6 1.14/.49 0.80/.23 0.89/.50 8 30 PO 8 M NTR SAL 5% 0-2 1.69/.01* 1.26/.22 1.17/.41 0-6 1.23/.05* 0.89/.29 0.90/.33 2-6 0.91/.57 0.70/.03* 0.76/.08 19 100 PO 8 M NTR SAL 5% 0-2 1.59/.00* 1.36/.02* 1.25/.11 0-6 1.28/.02* 1.02/.89 0.96/.74 2-6 1.02/.91 0.84/.44 0.81/.26 19 100 PO 8 M NTR SAL 5% 0-2 1.84/.00* 1.10/.61 0.98/.93 0-6 1.41/.02* 1.00/.99 0.86/.20 0-24 0.95/.33 1.05/.61 0.93/.37 2-6 1.09/.68 0.94/.70 0.78/.14 6-24 0.61/.00* 1.11/.52 1.02/.90 DOSE VOLUME SODIUM CULORIDE COMPOUND MG/KG ROUTE SPECIES LOAD TIME (ML/KG) (MEQ/KG) (MEQ/KG) 19 100 PO 8 M NTR SAL 5% 0-2 2.07/.02* 1.52/.10 1.35/.19 0-6 1.40/.01* 1.10/.38 1.01/.89 0-24 1.00/.95 0.94/.53 0.85/.09 2-6 0.90/.55 0.03/.30 0.79/.15 6-24 0.70/.01* 0.76/.10 0.63/.01* 19 30 PO 8 M NTR SAL 5% 0-2 1.55/.01* 1.64/.01* 1.51/.03* 0-6 1.39/.01* 1.38/.01* 1.28/.03* 0-24 1.06/.19 1.13/.20 1.06/.51 2-6 1.27/.10 1.22/.14 1.13/.32 6-24 0.82/.03* 0.01/.23 0.75/.07 19 10 PO 8 M NTR SAL 5% 0-2 0.97/.87 1.11/.63 1.04/.85 0-6 0.95/.73 1.02/.92 0.95/.76 0-24 0.98/.88 1.04/.82 0.98/.87 2-6 0.93/.77 0.96/.86 0.89/.57 6-24 1.01/.92 1.96/.77 1.01/.94 15 3 PO 8 M NTR SAL 5% 0-2 1.24/.37 1.29/.29 1.22/.41 0-6 1.02/.91 1.00/.99 0.97/.80 2-6 0.87/.48 0.87/.34 0.85/.21 The compounds of the present invention can be incorporated into pharmaceutically acceptable dosage forms such as suspensions, tablets, capsules, and the like for either immediate or sustained release. By combining- them with suitable carriers or diluents using conventional methods known in the art. In addition to the active agent and the carrier or diluent, the dosage forms may include various binders, excipients, fillers, or flavoring agents to provide a satisfactory formulation of the desired pharmaceutical preparation.

Claims (20)

1. A compound of the formula
wherein R1 and R2 are hydrogen, loweralkyl, haloloweralkyl, aralkyl, naphthyl, pyridyl, isoquinolyl, phthalazinyl, naphthyl or phenyl substituted by one or more hydrogen, halo, loweralkyl, lowercycloalkyl, haloloweralkyl, aminosulfonyl, amino, nitro, hydroxy, alkoxy, carboxy, alkoxycarbonyl, cycloalkoxycarbonyl, aminocarbonyl, diloweralkylaminocarbonyl or
wherein n is 4 or 5, R3 is hydrogen, loweralkyl or aryl, and R4 is hydrogen, acyl, amino or loweralkyl, with the proviso that R4 cannot be hydrogen or acetyl when R, and R2 are each H, loweralkyl or phenyl and R3 is hydrogen, and pharmaceutically acceptable acid addition salts thereof.
2. The compounds of Claim 1 wherein R, is halophenyl, R2 is loweralkyl, R3 is hydrogen and R4 is hydrogen.
3. The compound of Claim 2 wherein R, is fluorophenyl, R2 is methyl and R3 and R4 are both hydrogen.
4. The compound of Claim 2 wherein R, is fluorophenyl, and R2, R3 and R4 are all hydrogen.
5. A pharmaceutical composition for treating inflammation comprising as the essential active ingredient an effective amount of a compound represented by the structural formula
wherein R, and R2 are hydrogen, loweralkyl, haloloweralkyl, aralkyl, naphthyl, pyridyl, isoquinolyl, phthalazinyl, naphthyl or phenyl substituted by one or more hydrogen, halo, loweralkyl, lowercycloalkyl, haloloweralkyl, aminosulfonyl, amino, nitro, hydroxy, alkoxy, carboxy, alkoxycar bonyl, cycloalkoxycarbonyl, aminocarbonyl, diloweralkylaminocarbonyl or
wherein n is 4 or 5, R3 is hydrogen, loweralkyl or aryl, and R4 is hydrogen, acyl, amino or loweralkyl, with the proviso that R4 cannot be hydrogen or acetyl when R, and R2 are each H, loweralkyl or phenyl and R3 is hydrogen, or a pharmaceutically acceptable acid addition salts thereof, in admixture with a pharmaceutically acceptable carrier.
6. A composition of Claim 5 wherein R, is halophenyl, R2 is loweralkyl, R3 is hydrogen and R4 is hydrogen.
7. A composition of Claim 2 wherein R, is fluorophenyl, R2 is methyl and R3 and R4 are both hydrogen.
8. A composition of Claim 2 wherein R, is fluorophenyl, and R2, R3 and R4 are all hydrogen.
9. A compound represented by the structural formula
wherein R, and R2 are hydrogen, loweralkyl, lowercycloalkyl, aralkyl, aryl, aryl substituted by one or more hydrogen, halo, loweralkyl, lowercycloalkyl, haloloweralkyl, aminosulfonyl, nitro, hydroxy, alkoxy, carboxy, alkoxycarbonyl, cycloalkoxy carbonyl, aminocarbonyl, diloweralkylaminocarbonyl or
wherein n is 4 or 5, pyridyl, isoquinolyl or phthalazinyl, R3 is hydrogen, halogen, loweralkyl or aryl, and R4 is hydrogen, acyl, amino or loweralkyl, and the pharmaceutically acceptable acid addition salts thereof.
1 0. A compound represented by the structural formula
wherein R' and R2 are each hydrogen, alkyl, cycloalkyl or aryl, R3 is hydrogen or halogen, R4 is hydrogen or acyl, and pharmaceutically acceptable acid addition salts thereof.
11. A compound represented by the structural formula
wherein R1 and R2 are each hydrogen, lower alkyl or phenyl, R3 is hydrogen, chloro, bromo or iodo, and R4 is hydrogen or acetyl, and pharmaceutically acceptable acid addition salts thereof.
12. A compound of Claim 10 wherein R1 is methyl or phenyl, R2 is hydrogen, methyl, or ethyl, R3 is hydrogen chloro, bromo, or iodo, and R4 is hydrogen or acetyl.
1 3. A compound of Claim 11 wherein R1 is phenyl, and R2, R3 and R4 are each hydrogen.
14. A compound of Claim 11 wherein R1 is methyl, R2 iS methyl, Ras is chloro, and R4 is hydrogen, and the hydrochloride salt thereof.
1 5. A compound of Claim 11 wherein R1 is methyl, R2 is methyl, R3 is chloro, and R4 is acetyl, and the hydrochloride salt thereof.
1 6. A compound of Claim 1 2 wherein R' is phenyl, R2 is hydrogen, R3 is hydrogen, and R4 is acetyl.
1 7. A pharmaceutical compoition comprising as the essential active ingredient a compound represented by the structural formula
wherein R' and R2 are each hydrogen, alkyl, cycloalkyl or aryl, R3 is hydrogen or halogen, R4 is hydrogen or acyl, or a pharmaceutically acceptable acid addition salt thereof, in admixture with a pharmaceutically acceptable carrier.
18. A composition of Claim 16 wherein R' is methyl or phenyl, R2 is hydrogen, methyl, or ethyl, R3 is hydrogen, chloro, bromo, or iodo, and R4 is hydrogen or acetyl.
19. A composition of Claim 1 7 wherein the amount of said essential active ingredient is from about 5 mg. to 200 mg. in terms of dosage unit per day per kilogram of body weight.
20. The compound according to any one of the examples herein.
GB7926299A 1979-07-27 1979-07-27 Pyrazolyl amino imidazolines Withdrawn GB2054555A (en)

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US6080763A (en) * 1997-11-03 2000-06-27 Boehringer Ingelheim Pharmaceuticals, Inc. Aromatic heterocyclic compounds and their use as anti-inflammatory agents
WO2010101973A1 (en) * 2009-03-03 2010-09-10 E. I. Du Pont De Nemours And Company Fungicidal pyrazoles
WO2013126283A1 (en) * 2012-02-20 2013-08-29 E. I. Du Pont De Nemours And Company Fungicidal pyrazoles

Cited By (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6080763A (en) * 1997-11-03 2000-06-27 Boehringer Ingelheim Pharmaceuticals, Inc. Aromatic heterocyclic compounds and their use as anti-inflammatory agents
US9655361B2 (en) 2009-03-03 2017-05-23 E I Du Pont De Nemours And Company Fungicidal pyrazoles
CN102421756A (en) * 2009-03-03 2012-04-18 纳幕尔杜邦公司 Fungicidal pyrazoles
US9062005B2 (en) 2009-03-03 2015-06-23 E I Du Pont De Nemours And Company Fungicidal pyrazoles
JP2015172062A (en) * 2009-03-03 2015-10-01 イー・アイ・デュポン・ドウ・ヌムール・アンド・カンパニーＥ．Ｉ．Ｄｕ Ｐｏｎｔ Ｄｅ Ｎｅｍｏｕｒｓ Ａｎｄ Ｃｏｍｐａｎｙ Antifungal, anti-mold pyrazoles
RU2577247C2 (en) * 2009-03-03 2016-03-10 Е.И. Дюпон Де Немур Энд Компани Fungicidal pyrazoles
AU2010221440B2 (en) * 2009-03-03 2016-05-19 Fmc Corporation Fungicidal pyrazoles
TWI548344B (en) * 2009-03-03 2016-09-11 杜邦股份有限公司 Fungicidal pyrazoles
WO2010101973A1 (en) * 2009-03-03 2010-09-10 E. I. Du Pont De Nemours And Company Fungicidal pyrazoles
CN107011326A (en) * 2009-03-03 2017-08-04 纳幕尔杜邦公司 Fungicidal pyrazoles compound
US10448639B2 (en) 2009-03-03 2019-10-22 Fmc Corporation Fungicidal pyrazoles
CN107011326B (en) * 2009-03-03 2019-11-12 Fmc公司 Fungicidal pyrazoles compound
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