CA1122600A - Heterocyclic tetrahydro-1-alkyl-4-oxo-1h-imidazol-2- ylidene urea and phenyl esters of tetrahydro-1-alkyl-4-oxo-1h imidazol-2-ylidene carbamic acid compounds - Google Patents
Heterocyclic tetrahydro-1-alkyl-4-oxo-1h-imidazol-2- ylidene urea and phenyl esters of tetrahydro-1-alkyl-4-oxo-1h imidazol-2-ylidene carbamic acid compoundsInfo
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/20—Hypnotics; Sedatives
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
Abstract
ABSTRACT OF THE DISCLOSURE
Heterocyclic tetrahydro-1-alkyl-4-oxo-1H-imidazol-2-ylidene urea and compounds which are useful as anxiolytic agents in living animals and also some of which act to block acid secretions.
Heterocyclic tetrahydro-1-alkyl-4-oxo-1H-imidazol-2-ylidene urea and compounds which are useful as anxiolytic agents in living animals and also some of which act to block acid secretions.
Description
~ (3~
This invention relates to certain heterocyclic tetra-hydro-l-alkyl-4-oxo-lH-imidazol-2-ylidene urea and phenyl esters of tetrahydro-l-alkyl-4-oxo-lH-imidazol-2-ylidene carbamic acid compounds which have useful anxiolytic activity in living animals and also some of which act to block acid secretions.
The physiologically active compounds of the present invention are represented by the following formulas:
> = N-C-NH-Z ~ ~ ~ N-C-O -~I) (II) wherein R is a lower alkyl radical; Z is a pyridinyl, thienyl or furanyl radical or a pyridinyl, thienyl or furanyl radical substituted with l to 3 radicals independently selected from the group consisting of hydroxyl, lower alkoxy, lower alkyl, halogen, nitro (-N02), NRlR2, CONRlR2, lower haloalkyl, C02Rl where Rl and R2 are independently selected from hydrogen and lower alkyl; A and B are indepen-dently selected from hydrogen, lower alkyl, halogen, lower alkoxy, lower haloalkyl and nitro.
The term halogen or prefix halo is used herein to represent those halogens having an atomic weight of no more than 127 and include chloriner fluorine, bromine and iodine.
As used herein (unless otherwise specified) the term "lower alkyl" means a straight or branched chain alkyl radical having from l to 8 carbon atoms. Also, the terms Nlower alkoxy" and "lower haloalkyl" as used herein mean straight or branched chain alkoxy and haloalkyl radicals respectively having from l to 8 carbon atoms, unless otherwise specified.
;5~S~60o The compounds of formulas (I) and (II) may be used in the form of pharmaceutically acceptable acid-addition salts.
Suitable pharmaceutically acceptable salts include, for example, the hydrochlorides, hydrobromides, phosphates, sul-fates, citrates, acetates and maleates.
A more preferred group of compounds of the present invention are those wherein R in formula (I) is a straight or branched chain lower alkyl radical having from 1 to 5 carbon atoms; ~ is a pyridinyl, thienyl or furanyl radical or Z is a substituted pyridinyl, thienyl or furanyl radical selected from the group consistin~ of those represented by the formulas:
X ~ X
~y ~Y ~Y
wherein X and Y are radicals independently selected from the group consisting of hydrogen, hydroxyl,straight or branched chain al5coxy having 1 to 5 carbon atoms, straight or branched chain alkyl having 1 to 5 carbon atomsr haloqen, nitro, NRlR~, CONRlR2, straight or branched chain haloalkyl having 1 to 5 carbon atoms and C02Rl where Rl and R2 are independently selected from hydrogen and straight or branched chain alkyl having 1 to 5 carbon atoms.
The compounds of the present invention are further illustrated by the following formulas (III), (IV) and (V) where R, X and Y are as defined hereinabove: -= N-C-N ~ ( ~ = N-C-N ~ Y
(III) R X
= N-C-N
~IV) 6-)0 The urea nitrogen of formula (III) which is attached to the pyridine ring may be at the two, three, or four position of the pyridine nucleus and X and Y may be attached to any other open position on the pyridine ring. Similarly, in formulas (IV) and (V) the urea nitrogen may be attached to the two or three position of the thiophene or furan ring and the X
and Y substituents attached to any other unoccupied position on the heterocyclic ring. The compounds of formulas (I), (II), (III), (IV) and (V) may also exist in another tautomeric form as depicted in (VI~.
R
N \ H O H
I / ~ N-C-N-Z
O// ~ N Y
(VI) where R and Z are as defined hereinabove.
~ he compounds of the present invention can be pre-pared by the following two general procedures.
Procedure 1, as illustrated in the following equations, involves the reaction of one equivalent of the appropriate 2-iminoimida~olidin-4-one 1 with an equivalent amount of an aryl chloroformate 2 in an anhydrous aprotic organic solvent, such as tetrahydrofuran ~THF), toluene, and dioxane. An excess of a non-nucleophilic base such as tri-ethylamine, pyridine, sodium carbonate, or the like is also presentin the reaction mixture to scavage the liberated hydrogen chloride. The reacticn mixture is then stirred at temperatures ranging from 0 to 100C. for an appropriate time (1-48 hr.), filtered, and the filtrate concentrated to leave the carbamate 3 which is purified by conventional tech-niques (chromatography, recrystallization, or distillation).
It should be noted that the carbamates 3 are also active in the animal tests which are predictive of anxiolytic activity in humans.
11;~'~6()0 The carbamate 3 is then treated with an equimolar, excess, or less than equimolar amount of an appropriate amino-substituted heterocycle 4 or 4a [pyridine 4, thiophene 4a (D=S), or furan 4a (D=O)] either neat or in an anhydrous aprotic solvent such as N,N-dimethylformam;de (DMF), THF, dimethylsulfoxide, toluene and other similar organic solvents at temperatures ranging from 25 to 100C. for 1-48 hours.
R A R
~= NH + ~ base ~ ~ ~ = N-C-0 - ~
R " ~ ~S ~ ~ ~ = N-C-N
= N-C-0 ~ + H2Nt`N ~ y 6' N~ N
N ~ = N C0' 0 ~ >
3 4a 5a Where R, X and Y represent the same atoms or radicals as described hereinabove;
A = H, straight or branched chain alkyl (Cl to C5), F, Cl, Br, I, straight or branched chain alkoxy (Cl to C5) t CF3, NO2;
B = A;
D = O, S;
The product may be isolated by one of two general methods, a and b.
(a) By filtration of the reaction mixture and puri-fication of the collected solid by conventional techniques.
(b) If little or no solid is present at the comple-tion of the reaction, the reaction mixture is poured into a 5-10 fold excess of water. If a precipitate forms, it is collected and purified by conventional techniques. If an oil or no precipitate is evident, the mixture is extracted with a suitable organic solvent (chloroform, ethyl ether, ethyl acetate) and the combined organic extracts are concentrated and the residue purified by conventional means to give the desired product.
Procedure 2, as illustrated in the following equa-tions, involves the reaction of the appropriate 2-iminoimi-dazolidin-4-one 1 with an equivalent or slight excess of the appropriately substituted heterocyclic isocyanat~ ~6a, 6) in an anhydrous aprotic organic solvent such as DMF, dimethyl-sulfoxide (DMSO), ( ~ = NH ~ ~ NCO 3 ~ ~ = N-C-N ~
~ H N ~ N N y _ 6 5 OT or R X
OCN ~ Y ~ ~ - N-C-N ~ Y
O H
6a 5a 'Z~;OO
(where R, X, Y and D are as defined previously hereinabove) THF, toluene or any other similar solvent at temperatures of 25-100 for 1-10 hours. The product can be isolated by removal of the reaction solvents in vacuo and purification of the residue by conventional techniques or by pouring the reac~ion mix~ure into water and collecting the precipitated product. This collected product is purified by conventional procedures.
Several of the heterocyclic isocyanates 6, 6a are known, but, to the extent they are not, they may be prepared by well known methods described in the literature~ For example, the procedures described in the following papers may be used to prepare the above isocyanates; J. G. Lombardino and C. F.
Gerber, J. Med. Chem. 7, 97 (1964) or H. M. Singleton and W. R.
Edwards, Jr., J. Amer. Chem. Soc. 60, 54D (1938).
All of the reactants needed to prepare the compounds of the present invention are commercially available or can be readily prepared by well known methods described in the literature.
Procedure 1 described above is exemplified by the preparation of the following Examples I, III and IV to XIV.
~XAMPLE I
1-(6-methyl-2-pyridinyl)-3-(tetrahydro-1-methyl-4-oxo-lH-imidazol-2-ylidene)urea To a stirred suspension of 50 g (0.44 moles) of creatinine 7 in 600 mls. of anhydrous tetrahydrofuran (THF) was added 49.2 g (0.49 moles) of triethylamine and then dropwise 69.2 9 ~0.44 moles) of phenyl chloroformate over 1/2 hour. The mixture was then refluxed for 17 hrs.(hours) cooled and filtered to separate the solid material. The filtrate was concentrated and ()0 the residue triturated with 500 ml of ether-hexane (1:1). The solid which formed was chromatographed over silica gel using chloroform as the eluent. The fractions containing the product were combined and concentrated. The residue was again tritra-ted with 500 ml of ether-hexane (1:1) to give 21.2 g of the phenyl ester of tetrahydro-l-methyl-4-oxo-lH-imidazol-2-ylidene carbamic acid, 8, m.p. 129-132C. A pure sample of the O
o~ N ~ ~ OCOCl E ~ ~ ~ = N-C-O
H
CH3 ~ 0"~ j CH3 ~ ~ = N-C-O N N
H
carbamate 8 was obtained by recrystallization from acetonitrile and a final chromatography over silica gel using chloroform-ethyl acetate was the eluent. The resulting yellow solid 8 melte~ at 163-164C.
Anal- calcd- for CllHllN33 C, 56-65; H~ 4-75; N~
18.02. Found: C, 56.13 H, 4.94; N, 17.86 To 2.25 9 (9.6 mM) of the phenyl carbamate 8 in 10 ml of anhydrous DMF was added 1.04 9 (9.6 mM) of 2-amino-6-methyl-pyridine. After stirring the mixture for 4 hrs. at 50C., it was filtered to separate a solid which was recrystallized from methanol to give 1.4 g of 1-(6-methyl-2-pyridinyl)-3-~tetra-hydro~l-methyl-4-oxo-lH-imidazol-2-ylidene) urea 9 as a white solid, m.p. 202-203C. (dec.).
Anal. c 11 13 5 2 28.32. Found: C, 53.23; H, 5.11; N, 28.23 Procedure 2 described above is exemplified by the following Examples II and X~7 to XXIII.
EXAMPLE II
Procedure 2 described above is exemplified by the preparation of 1-(3 pyridinyl)-3-tetrahydro-1-methyl-4-oxo-lH-imidazol-2-ylidene) urea 11. To a solution of 2.13 g (17.8 mM) of 3-pyridinylisocyanate 10 in 30 ml of dimethylformamide was added 2.0 9 (17.8 mM) of creatinine 7. The mixture was stirred at 90~95C. for 3 hrs. and then cooled to form a precipi-tate. The solid was collected, washed with ether, and then chromatographed over silica gel using 5% methanol in chloroform as the eluent. The fractions containing the product were combined, treated with charcoal, filtered, and the filtrate diluted with ether to precipitate 1.1 9 of 1-(3-pyridinyl)-3-(tetra hydro-l-methyl-4-oxo 1~-imidazol-2-ylidene) urea 11 as N ~ ~ NCO ~ > = N-C-N
pale yellow crystals, m.p. 200-201C. (dec.).
Anal. calcd. for CloHllN5O2: , 30.03. Found: C, 51.21; H, 4.98; N, 30.04.
()O
EXAMPLE III
1-(2-Pyridinyl)-3-(tetrahydro-1-methyl-4-oxo-lH-imidazol-2-ylidene) urea A mixture of 2.7 9 (11.6 mM) of the phenyl ester of tetrahydro-l-methyl-4-oxo-lH-imidazol-2-ylidene carbamac acid 8 and 10.0 9 (106 mM) of 2-aminopyridine was heated at 90C.
for 1 hr. The excess amine was removed by vacuum distillation and the residue tritrated with 35 ml. ethanol, filtered and the collected solid recrystallized from ethyl acetate to give 1.19 of the above urea as a cream colored solid, m.p. 218C.
(dec.).
Anal. calcd. for CloHllN502n C, 30.03. Found: C, 51.41; H, 4.76; N, 30.09.
EXAMPLE IV
l-t4-Pyridinyl)-3-(tetrahydro-1-methyl-4-oxo-lH-imidazol-2-ylidene) urea A mixture of 4.0 9 (17 mM) of the phenyl ester of tetrahydro-l-methyl-4-oxo-lH-imidazol-2-ylidene carbamic acid 8 and 1.6 9 (17 mM) of 4-aminopyridine in 25 ml of anhydrous dimethylformamide (DMF) was heated at 55 for 5 hrs.(hours)~-cooled, and poured with stirring into 250 ml of water. The precipi-tated solid was collected, washed with ethanol and ether, and air dried. Recrystallization from methanol gave 2.0 9 of the above urea as a pale yellow solid, m.p. 218-220C. (dec.).
Anal- calcd- for ClOHllN52 C~ 51049 ~ 4-7 30.03. Found: C, 51.54; H, 4.95; N, 29.92 Z~OO
EXAMPLE V
1-(4-Methyl-2-pyridinyl)-3-(tetrahydro-1-methyl-4-oxo-lH-imidazol-2-ylidene) urea A mixture of 3.0 g (12.8 mM) of the phenyl carbamate 8 and 2.8 g (25.7 mM) of 2-amino-4-methylpyridine in 25 ml of anhydrous DMF was stirred at 25 C. for 5 hrs., filtered and the filtrate diluted with 150 ml of water. The resulting precipitate was collected and recrystallized from ethanol to give O.S g of the above urea as a pale yellow solid, m.p.
231-232C. (dec.).
Anal. calcd. for CllH13N5O2- C, 53.44; ~, 5.30, N, 28.32. Found: C, 53.56; H, 5.29; N, 28.39 EXAMPLE VI
1-(5-Methyl-2-pyridinyl)-3-(tetrahydro-1-methyl-4-oxo-lH-imidazol-2-ylidene) urea A mixture of 2.33 g (10.0 mM) of the phenyl carbamate 8 and 1.08 g 110.0 mM) of 2-amino-5-methylpyridine in 9 ml of anhydrou~ DMF was stirred at 70C. for 2 hrs., cooled and poured into water with stirrngO The resulting precipitate was collected, washed with water and then acetone to give 1.9 9 of the above urea as a pale yellow solid, m.p. 227C. (dec.)~
Anal. calcd. for CllH13N5O2, , : , 28.33. Found: C, 53.64; H, 5.49; N, 28.54 EXAMPLE VII
1-(4,6-Dimethyl-2-pyridinyl)-3-(tetrahydro-1-methyl-4-oxo-lH-imidazol-2-ylidene) urea A mi~ture of 3.0 9 (12.8 mM) of the phenyl carbamate 8, and 1.6 g (12.B mM) of 4,6-dimethyl-2-aminopyridine in 50 ml ()0 of anhydrous DMF was heated at 55C. for 8 hrs., cooled, and poured into 200 ml water. The resulting precipitate was collected and recrystallized from ethyl acetate to give 1.3 9 of the above urea as a light yellow solid, m.p. 192-193C.
Anal. calcd. for C12H15N5O2: , 26.80. Found: C, 54.99; H, 5.69; N, 26.51 EXAMPLE VIII
._ 1-(6-Hydroxy-2-pyridinyl)-3-(tetrahydro-1-methyl-4-oxo-lH-imidazol-2-ylidene) urea A mixture of 3.0 g (12.8 mM) of the phenyl carbamate 8 and 1.5 9 (12.8 mM) of 2-amino-6-hydroxypyridine in 25 ml of anhydrous DMF was heated at 85C. for 5 hrs., cooled, and poured into 100 ml of water. The resulting precipitate was collected, washed successively with water, ethanol; ethyl acetate, and ether. Recrystallization from ethanol gave 1.0 9 of the above urea as a yellow solid, m.p. 233-234C. (dec.).
Anal. calcd. for CloHllN5O3: C, 48.19; H, 4.45;
28.10. Found: C, 48.04; H, 4.71; N, 28.14 EXAMPLE IX
1-(2-Methoxy-5-pyridinyl)-3-(tetrahydro-1-methyl-4-oxo-lH-imidazol-2-ylidene) urea A mixture of 2.33 9 (10.0 mM~ of phenyl carbamate 8 and 1.24 9. (10.0 mM) of 5-amino-2-methoxypyridine in 9 ml of anhydrous DMF was heated at 70C. for 6 hrs., cooled, and poured into 40 ml of water. On cooling in ice, crystals pre-cipitated from the aqueous solution and these were collected and recrystallized from methanol to give 0.5 9 of the above urea as pale yellow needles, m.p. 175-176C.
Anal. calcd. for CllH13N5O3: C, 50.L8: H, 4.98; ~, 26.61. Found: C, 49.98; H, 5.14; N, 26.92 EXAMPLE X
1-(5-Chloro-2-pyridinyl)-3-(tetrahydro-1-methyl-4-oxo-lH-imidazol-2-ylidene) urea A mixture of 2.3 g. ~10 mM) of the phenyl carbamate 8 and 3.0 g. (23 mM) of 2-amino-5-chloropyridine in 25 ml of anhydrous DMF was heated at 45-50C. for 2 hrs., cooled and filtered. The collected solid was washed successively with cold DMF, ethyl acetate, and ether to give 1.6 9 of the above urea as a yellow solid, m.p. 250-251C. (dec.).
Anal. calcd. for CloHloClN5O2: C, 44.87; H, 3.77; N, 26.16; Cl, 13.25. Found: C, 44.77; H, 3.95; N, 26.22; Cl, 13.21 EXAMPLE XI
1-(5-Nitro-2-pyridinyl)-3-(tetrahydro-1-methyl-4-oxo lH-imidazol-2-ylidene) urea A mixture of 3.0 9 (12.8 mM) of the phenyl carbamate 8 and 1.8 9 (12.8 mM) of 2-amino-5-nitropyridine in 20 ml of anhydrous DMF was stirred at 25C. for 2 days. The reaction mixture was filtered and the collected solid washed succes-sively with cold DMF, ethyl acetate, and ether to give 1.0 g of the above urea as yellow solid, m.p. 225-227C. (dec.).
Anal. calcd. for CloHloN6O4: C, 43.17; ~, 3.6 ; N, 30.20. Found: C, 43.27; H, 3.93; N, 30.59 0~
EXAMPLE XII
1-~5-Aminocarbonyl-2-pyridinyl)-3-(tetrahydro-1-methyl-4-oxo-lH-imidazol-2-ylidene) urea A mixture of 1.00 9 (4.2g mM) of the phenyl carbamate 8 and 0.59 9 (4.29 mM) of 6-aminonicotinamide in 4 ml of anhy-drous DMF was stirred at 65C. for 1.5 hr., cooled and poured into water. The resulting precipitate was collected, washed with acetone and air dried to give 0.85 9 of the above urea as a pale yellow solid, m.p. 240-243C. (dec.).
Anal. calcd. for CllH12N6O3:
Found: C, 47.83 EXAMPLE XIII
1-(3-Methyl-2-pyridinyl)-3-(tetrahydro-1-methyl-4-oxo-lH-imidazol-2-ylidene) urea A mixture of 5.0 g (21~ 4 mM) of the phenyl carbamate 8 and 1.2 g (10.7 mM) of 2-amino-3-methyl-pyridine in 25 ml of anhydrous DMF was heated at 55 for 3 brs. and then cooled.
The solid was collected via filtration and washed successively with cold DMF, ethyl acetate and ether. Recrystallization from ethanol and a final wash with water gave 0.07 9 of the above urea as a pale yellow solid, m.p. 219-221C. (dec.).
Anal. calcd. for CllH13N5O2: C, 53.43; H, 5.30; N, 28.32. Found: C, 53.32; H, 5.36; N, 28.51 1~ 0 EXAMPLE XIV
1-(2-Dimethylamino-5-pyridinyl)-3-(tetrahydro-1-methyl-4-oxo-lH-imidazol-2-ylidene) urea A mixture of 8O1 9 (35 mM) of the phenyl carbamate 8 and 2.5 9 (23 mM) of s-amino-2-dimethylaminopyridine in 50 ml of anhydrous DMF was heated at 55 for 3.5 hrs. and then cooled and poured into 200 ml of water. The resulting mixture was extracted with three 100 ml portions of ethyl acetate and the combined extracts were dried (MgSO4), filtered and concentrated to a volume of 50 ml. The precipitate which formed was collected and recrystallized from acetone to give 0.84 of the above urea as tan crystals, m.p. 212-213C.
Anal. calcd. for C12H16N6O2: C, 30.42. Found: C, 52.04; H, 5.88; N, 30.07 EXAMPLE XV
l-(Tetrahydro~ methyl-4-oxo-lH-imidazol-2-ylidene)-3-(2-thienyl) urea To 9.4 g (83 mM) of creatinine in 100 ml of anhydrous DMF was added with stirring of solution of 9.2 g (75 mM)
This invention relates to certain heterocyclic tetra-hydro-l-alkyl-4-oxo-lH-imidazol-2-ylidene urea and phenyl esters of tetrahydro-l-alkyl-4-oxo-lH-imidazol-2-ylidene carbamic acid compounds which have useful anxiolytic activity in living animals and also some of which act to block acid secretions.
The physiologically active compounds of the present invention are represented by the following formulas:
> = N-C-NH-Z ~ ~ ~ N-C-O -~I) (II) wherein R is a lower alkyl radical; Z is a pyridinyl, thienyl or furanyl radical or a pyridinyl, thienyl or furanyl radical substituted with l to 3 radicals independently selected from the group consisting of hydroxyl, lower alkoxy, lower alkyl, halogen, nitro (-N02), NRlR2, CONRlR2, lower haloalkyl, C02Rl where Rl and R2 are independently selected from hydrogen and lower alkyl; A and B are indepen-dently selected from hydrogen, lower alkyl, halogen, lower alkoxy, lower haloalkyl and nitro.
The term halogen or prefix halo is used herein to represent those halogens having an atomic weight of no more than 127 and include chloriner fluorine, bromine and iodine.
As used herein (unless otherwise specified) the term "lower alkyl" means a straight or branched chain alkyl radical having from l to 8 carbon atoms. Also, the terms Nlower alkoxy" and "lower haloalkyl" as used herein mean straight or branched chain alkoxy and haloalkyl radicals respectively having from l to 8 carbon atoms, unless otherwise specified.
;5~S~60o The compounds of formulas (I) and (II) may be used in the form of pharmaceutically acceptable acid-addition salts.
Suitable pharmaceutically acceptable salts include, for example, the hydrochlorides, hydrobromides, phosphates, sul-fates, citrates, acetates and maleates.
A more preferred group of compounds of the present invention are those wherein R in formula (I) is a straight or branched chain lower alkyl radical having from 1 to 5 carbon atoms; ~ is a pyridinyl, thienyl or furanyl radical or Z is a substituted pyridinyl, thienyl or furanyl radical selected from the group consistin~ of those represented by the formulas:
X ~ X
~y ~Y ~Y
wherein X and Y are radicals independently selected from the group consisting of hydrogen, hydroxyl,straight or branched chain al5coxy having 1 to 5 carbon atoms, straight or branched chain alkyl having 1 to 5 carbon atomsr haloqen, nitro, NRlR~, CONRlR2, straight or branched chain haloalkyl having 1 to 5 carbon atoms and C02Rl where Rl and R2 are independently selected from hydrogen and straight or branched chain alkyl having 1 to 5 carbon atoms.
The compounds of the present invention are further illustrated by the following formulas (III), (IV) and (V) where R, X and Y are as defined hereinabove: -= N-C-N ~ ( ~ = N-C-N ~ Y
(III) R X
= N-C-N
~IV) 6-)0 The urea nitrogen of formula (III) which is attached to the pyridine ring may be at the two, three, or four position of the pyridine nucleus and X and Y may be attached to any other open position on the pyridine ring. Similarly, in formulas (IV) and (V) the urea nitrogen may be attached to the two or three position of the thiophene or furan ring and the X
and Y substituents attached to any other unoccupied position on the heterocyclic ring. The compounds of formulas (I), (II), (III), (IV) and (V) may also exist in another tautomeric form as depicted in (VI~.
R
N \ H O H
I / ~ N-C-N-Z
O// ~ N Y
(VI) where R and Z are as defined hereinabove.
~ he compounds of the present invention can be pre-pared by the following two general procedures.
Procedure 1, as illustrated in the following equations, involves the reaction of one equivalent of the appropriate 2-iminoimida~olidin-4-one 1 with an equivalent amount of an aryl chloroformate 2 in an anhydrous aprotic organic solvent, such as tetrahydrofuran ~THF), toluene, and dioxane. An excess of a non-nucleophilic base such as tri-ethylamine, pyridine, sodium carbonate, or the like is also presentin the reaction mixture to scavage the liberated hydrogen chloride. The reacticn mixture is then stirred at temperatures ranging from 0 to 100C. for an appropriate time (1-48 hr.), filtered, and the filtrate concentrated to leave the carbamate 3 which is purified by conventional tech-niques (chromatography, recrystallization, or distillation).
It should be noted that the carbamates 3 are also active in the animal tests which are predictive of anxiolytic activity in humans.
11;~'~6()0 The carbamate 3 is then treated with an equimolar, excess, or less than equimolar amount of an appropriate amino-substituted heterocycle 4 or 4a [pyridine 4, thiophene 4a (D=S), or furan 4a (D=O)] either neat or in an anhydrous aprotic solvent such as N,N-dimethylformam;de (DMF), THF, dimethylsulfoxide, toluene and other similar organic solvents at temperatures ranging from 25 to 100C. for 1-48 hours.
R A R
~= NH + ~ base ~ ~ ~ = N-C-0 - ~
R " ~ ~S ~ ~ ~ = N-C-N
= N-C-0 ~ + H2Nt`N ~ y 6' N~ N
N ~ = N C0' 0 ~ >
3 4a 5a Where R, X and Y represent the same atoms or radicals as described hereinabove;
A = H, straight or branched chain alkyl (Cl to C5), F, Cl, Br, I, straight or branched chain alkoxy (Cl to C5) t CF3, NO2;
B = A;
D = O, S;
The product may be isolated by one of two general methods, a and b.
(a) By filtration of the reaction mixture and puri-fication of the collected solid by conventional techniques.
(b) If little or no solid is present at the comple-tion of the reaction, the reaction mixture is poured into a 5-10 fold excess of water. If a precipitate forms, it is collected and purified by conventional techniques. If an oil or no precipitate is evident, the mixture is extracted with a suitable organic solvent (chloroform, ethyl ether, ethyl acetate) and the combined organic extracts are concentrated and the residue purified by conventional means to give the desired product.
Procedure 2, as illustrated in the following equa-tions, involves the reaction of the appropriate 2-iminoimi-dazolidin-4-one 1 with an equivalent or slight excess of the appropriately substituted heterocyclic isocyanat~ ~6a, 6) in an anhydrous aprotic organic solvent such as DMF, dimethyl-sulfoxide (DMSO), ( ~ = NH ~ ~ NCO 3 ~ ~ = N-C-N ~
~ H N ~ N N y _ 6 5 OT or R X
OCN ~ Y ~ ~ - N-C-N ~ Y
O H
6a 5a 'Z~;OO
(where R, X, Y and D are as defined previously hereinabove) THF, toluene or any other similar solvent at temperatures of 25-100 for 1-10 hours. The product can be isolated by removal of the reaction solvents in vacuo and purification of the residue by conventional techniques or by pouring the reac~ion mix~ure into water and collecting the precipitated product. This collected product is purified by conventional procedures.
Several of the heterocyclic isocyanates 6, 6a are known, but, to the extent they are not, they may be prepared by well known methods described in the literature~ For example, the procedures described in the following papers may be used to prepare the above isocyanates; J. G. Lombardino and C. F.
Gerber, J. Med. Chem. 7, 97 (1964) or H. M. Singleton and W. R.
Edwards, Jr., J. Amer. Chem. Soc. 60, 54D (1938).
All of the reactants needed to prepare the compounds of the present invention are commercially available or can be readily prepared by well known methods described in the literature.
Procedure 1 described above is exemplified by the preparation of the following Examples I, III and IV to XIV.
~XAMPLE I
1-(6-methyl-2-pyridinyl)-3-(tetrahydro-1-methyl-4-oxo-lH-imidazol-2-ylidene)urea To a stirred suspension of 50 g (0.44 moles) of creatinine 7 in 600 mls. of anhydrous tetrahydrofuran (THF) was added 49.2 g (0.49 moles) of triethylamine and then dropwise 69.2 9 ~0.44 moles) of phenyl chloroformate over 1/2 hour. The mixture was then refluxed for 17 hrs.(hours) cooled and filtered to separate the solid material. The filtrate was concentrated and ()0 the residue triturated with 500 ml of ether-hexane (1:1). The solid which formed was chromatographed over silica gel using chloroform as the eluent. The fractions containing the product were combined and concentrated. The residue was again tritra-ted with 500 ml of ether-hexane (1:1) to give 21.2 g of the phenyl ester of tetrahydro-l-methyl-4-oxo-lH-imidazol-2-ylidene carbamic acid, 8, m.p. 129-132C. A pure sample of the O
o~ N ~ ~ OCOCl E ~ ~ ~ = N-C-O
H
CH3 ~ 0"~ j CH3 ~ ~ = N-C-O N N
H
carbamate 8 was obtained by recrystallization from acetonitrile and a final chromatography over silica gel using chloroform-ethyl acetate was the eluent. The resulting yellow solid 8 melte~ at 163-164C.
Anal- calcd- for CllHllN33 C, 56-65; H~ 4-75; N~
18.02. Found: C, 56.13 H, 4.94; N, 17.86 To 2.25 9 (9.6 mM) of the phenyl carbamate 8 in 10 ml of anhydrous DMF was added 1.04 9 (9.6 mM) of 2-amino-6-methyl-pyridine. After stirring the mixture for 4 hrs. at 50C., it was filtered to separate a solid which was recrystallized from methanol to give 1.4 g of 1-(6-methyl-2-pyridinyl)-3-~tetra-hydro~l-methyl-4-oxo-lH-imidazol-2-ylidene) urea 9 as a white solid, m.p. 202-203C. (dec.).
Anal. c 11 13 5 2 28.32. Found: C, 53.23; H, 5.11; N, 28.23 Procedure 2 described above is exemplified by the following Examples II and X~7 to XXIII.
EXAMPLE II
Procedure 2 described above is exemplified by the preparation of 1-(3 pyridinyl)-3-tetrahydro-1-methyl-4-oxo-lH-imidazol-2-ylidene) urea 11. To a solution of 2.13 g (17.8 mM) of 3-pyridinylisocyanate 10 in 30 ml of dimethylformamide was added 2.0 9 (17.8 mM) of creatinine 7. The mixture was stirred at 90~95C. for 3 hrs. and then cooled to form a precipi-tate. The solid was collected, washed with ether, and then chromatographed over silica gel using 5% methanol in chloroform as the eluent. The fractions containing the product were combined, treated with charcoal, filtered, and the filtrate diluted with ether to precipitate 1.1 9 of 1-(3-pyridinyl)-3-(tetra hydro-l-methyl-4-oxo 1~-imidazol-2-ylidene) urea 11 as N ~ ~ NCO ~ > = N-C-N
pale yellow crystals, m.p. 200-201C. (dec.).
Anal. calcd. for CloHllN5O2: , 30.03. Found: C, 51.21; H, 4.98; N, 30.04.
()O
EXAMPLE III
1-(2-Pyridinyl)-3-(tetrahydro-1-methyl-4-oxo-lH-imidazol-2-ylidene) urea A mixture of 2.7 9 (11.6 mM) of the phenyl ester of tetrahydro-l-methyl-4-oxo-lH-imidazol-2-ylidene carbamac acid 8 and 10.0 9 (106 mM) of 2-aminopyridine was heated at 90C.
for 1 hr. The excess amine was removed by vacuum distillation and the residue tritrated with 35 ml. ethanol, filtered and the collected solid recrystallized from ethyl acetate to give 1.19 of the above urea as a cream colored solid, m.p. 218C.
(dec.).
Anal. calcd. for CloHllN502n C, 30.03. Found: C, 51.41; H, 4.76; N, 30.09.
EXAMPLE IV
l-t4-Pyridinyl)-3-(tetrahydro-1-methyl-4-oxo-lH-imidazol-2-ylidene) urea A mixture of 4.0 9 (17 mM) of the phenyl ester of tetrahydro-l-methyl-4-oxo-lH-imidazol-2-ylidene carbamic acid 8 and 1.6 9 (17 mM) of 4-aminopyridine in 25 ml of anhydrous dimethylformamide (DMF) was heated at 55 for 5 hrs.(hours)~-cooled, and poured with stirring into 250 ml of water. The precipi-tated solid was collected, washed with ethanol and ether, and air dried. Recrystallization from methanol gave 2.0 9 of the above urea as a pale yellow solid, m.p. 218-220C. (dec.).
Anal- calcd- for ClOHllN52 C~ 51049 ~ 4-7 30.03. Found: C, 51.54; H, 4.95; N, 29.92 Z~OO
EXAMPLE V
1-(4-Methyl-2-pyridinyl)-3-(tetrahydro-1-methyl-4-oxo-lH-imidazol-2-ylidene) urea A mixture of 3.0 g (12.8 mM) of the phenyl carbamate 8 and 2.8 g (25.7 mM) of 2-amino-4-methylpyridine in 25 ml of anhydrous DMF was stirred at 25 C. for 5 hrs., filtered and the filtrate diluted with 150 ml of water. The resulting precipitate was collected and recrystallized from ethanol to give O.S g of the above urea as a pale yellow solid, m.p.
231-232C. (dec.).
Anal. calcd. for CllH13N5O2- C, 53.44; ~, 5.30, N, 28.32. Found: C, 53.56; H, 5.29; N, 28.39 EXAMPLE VI
1-(5-Methyl-2-pyridinyl)-3-(tetrahydro-1-methyl-4-oxo-lH-imidazol-2-ylidene) urea A mixture of 2.33 g (10.0 mM) of the phenyl carbamate 8 and 1.08 g 110.0 mM) of 2-amino-5-methylpyridine in 9 ml of anhydrou~ DMF was stirred at 70C. for 2 hrs., cooled and poured into water with stirrngO The resulting precipitate was collected, washed with water and then acetone to give 1.9 9 of the above urea as a pale yellow solid, m.p. 227C. (dec.)~
Anal. calcd. for CllH13N5O2, , : , 28.33. Found: C, 53.64; H, 5.49; N, 28.54 EXAMPLE VII
1-(4,6-Dimethyl-2-pyridinyl)-3-(tetrahydro-1-methyl-4-oxo-lH-imidazol-2-ylidene) urea A mi~ture of 3.0 9 (12.8 mM) of the phenyl carbamate 8, and 1.6 g (12.B mM) of 4,6-dimethyl-2-aminopyridine in 50 ml ()0 of anhydrous DMF was heated at 55C. for 8 hrs., cooled, and poured into 200 ml water. The resulting precipitate was collected and recrystallized from ethyl acetate to give 1.3 9 of the above urea as a light yellow solid, m.p. 192-193C.
Anal. calcd. for C12H15N5O2: , 26.80. Found: C, 54.99; H, 5.69; N, 26.51 EXAMPLE VIII
._ 1-(6-Hydroxy-2-pyridinyl)-3-(tetrahydro-1-methyl-4-oxo-lH-imidazol-2-ylidene) urea A mixture of 3.0 g (12.8 mM) of the phenyl carbamate 8 and 1.5 9 (12.8 mM) of 2-amino-6-hydroxypyridine in 25 ml of anhydrous DMF was heated at 85C. for 5 hrs., cooled, and poured into 100 ml of water. The resulting precipitate was collected, washed successively with water, ethanol; ethyl acetate, and ether. Recrystallization from ethanol gave 1.0 9 of the above urea as a yellow solid, m.p. 233-234C. (dec.).
Anal. calcd. for CloHllN5O3: C, 48.19; H, 4.45;
28.10. Found: C, 48.04; H, 4.71; N, 28.14 EXAMPLE IX
1-(2-Methoxy-5-pyridinyl)-3-(tetrahydro-1-methyl-4-oxo-lH-imidazol-2-ylidene) urea A mixture of 2.33 9 (10.0 mM~ of phenyl carbamate 8 and 1.24 9. (10.0 mM) of 5-amino-2-methoxypyridine in 9 ml of anhydrous DMF was heated at 70C. for 6 hrs., cooled, and poured into 40 ml of water. On cooling in ice, crystals pre-cipitated from the aqueous solution and these were collected and recrystallized from methanol to give 0.5 9 of the above urea as pale yellow needles, m.p. 175-176C.
Anal. calcd. for CllH13N5O3: C, 50.L8: H, 4.98; ~, 26.61. Found: C, 49.98; H, 5.14; N, 26.92 EXAMPLE X
1-(5-Chloro-2-pyridinyl)-3-(tetrahydro-1-methyl-4-oxo-lH-imidazol-2-ylidene) urea A mixture of 2.3 g. ~10 mM) of the phenyl carbamate 8 and 3.0 g. (23 mM) of 2-amino-5-chloropyridine in 25 ml of anhydrous DMF was heated at 45-50C. for 2 hrs., cooled and filtered. The collected solid was washed successively with cold DMF, ethyl acetate, and ether to give 1.6 9 of the above urea as a yellow solid, m.p. 250-251C. (dec.).
Anal. calcd. for CloHloClN5O2: C, 44.87; H, 3.77; N, 26.16; Cl, 13.25. Found: C, 44.77; H, 3.95; N, 26.22; Cl, 13.21 EXAMPLE XI
1-(5-Nitro-2-pyridinyl)-3-(tetrahydro-1-methyl-4-oxo lH-imidazol-2-ylidene) urea A mixture of 3.0 9 (12.8 mM) of the phenyl carbamate 8 and 1.8 9 (12.8 mM) of 2-amino-5-nitropyridine in 20 ml of anhydrous DMF was stirred at 25C. for 2 days. The reaction mixture was filtered and the collected solid washed succes-sively with cold DMF, ethyl acetate, and ether to give 1.0 g of the above urea as yellow solid, m.p. 225-227C. (dec.).
Anal. calcd. for CloHloN6O4: C, 43.17; ~, 3.6 ; N, 30.20. Found: C, 43.27; H, 3.93; N, 30.59 0~
EXAMPLE XII
1-~5-Aminocarbonyl-2-pyridinyl)-3-(tetrahydro-1-methyl-4-oxo-lH-imidazol-2-ylidene) urea A mixture of 1.00 9 (4.2g mM) of the phenyl carbamate 8 and 0.59 9 (4.29 mM) of 6-aminonicotinamide in 4 ml of anhy-drous DMF was stirred at 65C. for 1.5 hr., cooled and poured into water. The resulting precipitate was collected, washed with acetone and air dried to give 0.85 9 of the above urea as a pale yellow solid, m.p. 240-243C. (dec.).
Anal. calcd. for CllH12N6O3:
Found: C, 47.83 EXAMPLE XIII
1-(3-Methyl-2-pyridinyl)-3-(tetrahydro-1-methyl-4-oxo-lH-imidazol-2-ylidene) urea A mixture of 5.0 g (21~ 4 mM) of the phenyl carbamate 8 and 1.2 g (10.7 mM) of 2-amino-3-methyl-pyridine in 25 ml of anhydrous DMF was heated at 55 for 3 brs. and then cooled.
The solid was collected via filtration and washed successively with cold DMF, ethyl acetate and ether. Recrystallization from ethanol and a final wash with water gave 0.07 9 of the above urea as a pale yellow solid, m.p. 219-221C. (dec.).
Anal. calcd. for CllH13N5O2: C, 53.43; H, 5.30; N, 28.32. Found: C, 53.32; H, 5.36; N, 28.51 1~ 0 EXAMPLE XIV
1-(2-Dimethylamino-5-pyridinyl)-3-(tetrahydro-1-methyl-4-oxo-lH-imidazol-2-ylidene) urea A mixture of 8O1 9 (35 mM) of the phenyl carbamate 8 and 2.5 9 (23 mM) of s-amino-2-dimethylaminopyridine in 50 ml of anhydrous DMF was heated at 55 for 3.5 hrs. and then cooled and poured into 200 ml of water. The resulting mixture was extracted with three 100 ml portions of ethyl acetate and the combined extracts were dried (MgSO4), filtered and concentrated to a volume of 50 ml. The precipitate which formed was collected and recrystallized from acetone to give 0.84 of the above urea as tan crystals, m.p. 212-213C.
Anal. calcd. for C12H16N6O2: C, 30.42. Found: C, 52.04; H, 5.88; N, 30.07 EXAMPLE XV
l-(Tetrahydro~ methyl-4-oxo-lH-imidazol-2-ylidene)-3-(2-thienyl) urea To 9.4 g (83 mM) of creatinine in 100 ml of anhydrous DMF was added with stirring of solution of 9.2 g (75 mM)
2-thienyl isocyanate in 60 ml of tolue~e. After the addition was completed, the mix~ure was stirred at 55C. for 1 hr., cooled, and the solvents removed in vaCuQ. The residue was recrystallized first from ethanol and then ethyl acetate (treated with charcoal) to give 5.3 g of the above urea as an off-white solid, m.p. 191-192C. (dec.).
Anal. calcd. for Cg~loN~O2S C, 45.37; H, 4.23; N, 23.51. Found: C,45.46; H, 4.40; N~ 23059 ()o -16~
EXAMPLE XVI
l-(Tetrahydro-l-methyl-4-oxo-lH-imidazol-2-ylidene)-3-(3-thienyl) urea To a stirred suspension of 2.6 9 ~23 mM) of creati-nine in 50 ml of anhydrous DMF was added a solution of 3.0 g (23 mM) of 3-thienyl isocyanate in 25 ml of toluene. The resulting mixture was heated at 75C. for 4.5 hrs., cooled and added to 150 ml of water. The resulting precipitate was collected and recrystallized from ethyl acetate to give 1.4 g of the above urea as a cream colored solid, m.p. 194-195C.
Anal. calcd. for CgHloN4O2S: C, 45.37; H, 4.23; N, 23.51. Found: C, 44.96; H, 4.39; N, 23.67 EXAMPLE XVII
1-(4-Chloro-2-thienyl)-3-(tetrahydro-1-methyl-4-oxo-lH-imidazol-2-ylidene) urea To 3.0 9 (26.5 mM~ of creatinine in 50 ml of anhy-drous DMF was added with stirring a solution of 4-chloro-2-thi-enyl isocyanate in 25 ml of toluene. After stirring at 65C.
for 5 hrs., the mixture was cooled, added to 200 ml of water and filtered to separate a precipitate! which was recrystal-lized from ethanol and then ethyl acetate to give 1.0 g of the above urea as a light tan solid, m.p. 203-204C. (dec.) containing 1/8 mole of ethyl acetate of recrystallization.
Anal. calcd. for CgHgN4C102S.1/8 C4H8O2: C, 40.22; H, 3.55; N, 19.75. Found: C, 40.10; H, 3.84; N, 20.02 o EXAMPLE XVIII
1-(5-Methyl-2-thienyl)-3-(tetrahydro-1-methyl-4-oxo-lH-imidazol-2-ylidene) urea To 1.44 g (12 8 mM) of creatinine in 25 ml of anhy-drous DMF was added with stirring 1.78 9 (12.8 mM) of 5-methyl-2-thienyl isocyanate in 12 ml of toluene. After 6 hrs. at 60C., the mixture was cooled, poured into 100 ml of water and filtered. The collected solid was recrystallized twice from ethyl acetate to give 2.4 g of the above urea as a yellow-orange solid, m.p. 207-209C.
Ana calcd. for CloH12N42S
22.21. Found: C, 47.57; H, 4.76; N, 22.31 EXAMPLE XIX
1-~3-Methyl-2-thienyl)-3-(tetrahydro-1-methyl-4 oxo-lH-imidazol-2-ylidene) urea To a stirred suspension of 3.0 g (26.0 mM) of creati-rine in 50 ml anhydrous DMF was added dropwise a solution of
Anal. calcd. for Cg~loN~O2S C, 45.37; H, 4.23; N, 23.51. Found: C,45.46; H, 4.40; N~ 23059 ()o -16~
EXAMPLE XVI
l-(Tetrahydro-l-methyl-4-oxo-lH-imidazol-2-ylidene)-3-(3-thienyl) urea To a stirred suspension of 2.6 9 ~23 mM) of creati-nine in 50 ml of anhydrous DMF was added a solution of 3.0 g (23 mM) of 3-thienyl isocyanate in 25 ml of toluene. The resulting mixture was heated at 75C. for 4.5 hrs., cooled and added to 150 ml of water. The resulting precipitate was collected and recrystallized from ethyl acetate to give 1.4 g of the above urea as a cream colored solid, m.p. 194-195C.
Anal. calcd. for CgHloN4O2S: C, 45.37; H, 4.23; N, 23.51. Found: C, 44.96; H, 4.39; N, 23.67 EXAMPLE XVII
1-(4-Chloro-2-thienyl)-3-(tetrahydro-1-methyl-4-oxo-lH-imidazol-2-ylidene) urea To 3.0 9 (26.5 mM~ of creatinine in 50 ml of anhy-drous DMF was added with stirring a solution of 4-chloro-2-thi-enyl isocyanate in 25 ml of toluene. After stirring at 65C.
for 5 hrs., the mixture was cooled, added to 200 ml of water and filtered to separate a precipitate! which was recrystal-lized from ethanol and then ethyl acetate to give 1.0 g of the above urea as a light tan solid, m.p. 203-204C. (dec.) containing 1/8 mole of ethyl acetate of recrystallization.
Anal. calcd. for CgHgN4C102S.1/8 C4H8O2: C, 40.22; H, 3.55; N, 19.75. Found: C, 40.10; H, 3.84; N, 20.02 o EXAMPLE XVIII
1-(5-Methyl-2-thienyl)-3-(tetrahydro-1-methyl-4-oxo-lH-imidazol-2-ylidene) urea To 1.44 g (12 8 mM) of creatinine in 25 ml of anhy-drous DMF was added with stirring 1.78 9 (12.8 mM) of 5-methyl-2-thienyl isocyanate in 12 ml of toluene. After 6 hrs. at 60C., the mixture was cooled, poured into 100 ml of water and filtered. The collected solid was recrystallized twice from ethyl acetate to give 2.4 g of the above urea as a yellow-orange solid, m.p. 207-209C.
Ana calcd. for CloH12N42S
22.21. Found: C, 47.57; H, 4.76; N, 22.31 EXAMPLE XIX
1-~3-Methyl-2-thienyl)-3-(tetrahydro-1-methyl-4 oxo-lH-imidazol-2-ylidene) urea To a stirred suspension of 3.0 g (26.0 mM) of creati-rine in 50 ml anhydrous DMF was added dropwise a solution of
3.7 g (26 mM) of 3-methyl-2-thienyl isocyanate in 35 ml of toluene. After stirring at 90C. for 6 hrs., the reaction mixture was cooled and poured into 100 ml of water. The sepa-rated solid was collected, washed with water and recrystallized from ethyl ace~ate to give 1.2 g of the above urea as a grey-white solid, m.p. 201-202C.
Anal. calcd. for CloHl2N4o2s: ~
22.21. Found: C, 47.76; H, 4.83; N, 22.25 11;~'c:6()0 EXAMPLE XX
1-(5-Bromo-2-thienyl)-3-(tetrahydro-1-methyl-
Anal. calcd. for CloHl2N4o2s: ~
22.21. Found: C, 47.76; H, 4.83; N, 22.25 11;~'c:6()0 EXAMPLE XX
1-(5-Bromo-2-thienyl)-3-(tetrahydro-1-methyl-
4-oxo-lH-imidazol-2-ylidene) urea To a stirred suspension of 3.0 g (26 mM) of creati-nine in 30 ml of anhydrous DMF was added a solution of S.0 9 (26.5 mM) of 5-bromo-2-thienyl isocyanate in 15 ml of toluene.
The resul~ing mixture was heated at 75C. for 3 hrs., cooled, and poured into 200 ml of water. The precipitate was collec-ted, washed with ethanol and ether, and air-dried. The solid was dissolved in 250 ml hot acetone, treated with charcoal, filtered, and the filtrate diluted with water (250 ml). The resulting precipitate was collected, washed with acetone and then ether. Air-drying gave 2.3 9 of the above urea as a buff powder, m.p. 192-193C~ (dec.).
Anal. calcd. for CgHgBrN4O2S: C, 34.08; H, 2.86; N, 17.66. Found C, 33.94; H, 3.04; N, 17.30 EXAMPLE XXI
1-(5-Methoxy-2-thienyl)-3-(tetrahydro-1-methyl-4-oxo-lH-imidazol-2-ylidene) urea To a stirred suspension of 3.0 9 (26 mM) of creati-nine in 25 ml of anhydrous DMF was added a solution of 4.1 9 (26 T~M) of 5-methoxy-2-thienyl isocyanate in 20 ml of toluene.
The resulting mixture was heated at 65C. for 4.5 hrs., cooled, and poured into 200 ml of water. The mixture was extracted with ethyl acetate, and the combined extracts dried (MgSO4) and concentrated. The residue was recrystallized from e~hyl acetate and then ethanol. Final purification was accomplished by chromatography over silica gel ~ethyl acetate as eluant), decolorizing the product with charcoal, concentra-tion and recrystallization froTn acetone-hexane to give 0.23 9 of the above urea as a light brown solid, m.p. 180-182C.
~dec.).
i()V
Anal- calcd- for ClOH12N43S C, 44-78; H~ 4-51;
20.88. Found: C, 44.71; H, 4.67; N, 20.88 EXAMPLE XXII
1-(2-Furanyl-3-(tetrahydro-1-methyl-4-oxo-lH-imidazol-2-ylidene) urea To a stirred mixture of 6.9 g (60 mM) of creatinine in 100 ml of anhydrous ~MF was added a solution of 6.5 g (60 mM) of 2-furanyl isocyanate in 75 ml of toluene. After stirring the mixture 1 hr. at 25C. and then 1 hr. at 55C., the solvents were emoved in vacuo and the residue taken up in ethyl acetate and washed with water. The solvent was removed and the residue chromatographed over silica gel using ether-ethyl acetate (4:1) as the eluant. The fractions containing the product were combined and concentrated to leave 1.1 g of the above urea as an off-white solid, m.p.
173-175C. (dec.) Anal. calcd. for CgHloN4O3: C, 48.65; H, 4.53: N, 25.21. Found: C, 48.54; H, 4072; N, 24.92 EX~MPLE XXIII
1-(3-Furanyl-3-(tetrahydro-1-methyl-4-oxo-lH-imidazol-2-ylidene) urea To a stirred mixture of 18.3 9 (162 mM) of creatinine in 120 ml of anhydrous DMF was added a solution of 17.2 g (162 mM) of 3-furanyl isocyanate in 80 ml of toluene. After stirring the mixture for 3 hrs. at 65C., the mixture was partially concentrated under vacuum and the residue poured into 1200 ml of water. The resulting precipitate was collected, washed with water and recrystallized from e~hyl acetate. The solid was then chroma~ographed over silica gel using ethyl acetate as the eluant and the fractions containing the product were concentrated and the residue recrystallized from toluene to give 0.5 9 of the above urea as a tan solid, m.p.
179-181C. (dec.).
Anal. calcd. for CgHloN4O3: C, 48.65; H, 4.53; N, 25.21. Found: C, 48.85; H, 4.68 N, 25.17 To further illustrate the preparation of the com-pounds of the present invention l-(tetrahydro-l-methyl-4-oxo-lH-imidazol-2-ylidene)-3-(6-trifluoromethyl-2-pyridinyl)urea, 1-(4-chloro-6-methyl-2-pyridinyl)-3-(tetrahydro-1-ethyl-4-oxo-lH-imidazol-2-ylidene)urea, 1-(5-carboxyl-2-pyridinyl)-3-(tetra-hydro-l-isopropyl-4-oxo-lH-imidazol-2-ylidene)urea, and 1-(2-pyridinyl)-3-(tetrahydro-1-pentyl-4-oxo-1~-imidazol-2-yli-dene)urea can be prepared by the method of Example VI by using the equivalent amount of the appropriate phenyl ester of tetrahydro-l-alkyl-4-oxo-lH-imidazol-2-ylidene carbamic acid and the appropriate substituted aminopyridine as reactants.
1-(3-methyl-2-furanyl)-3-(tetrahydro-1-ethyl-4-oxo-lH-m imidazol-2-ylidene)urea, 1-(tetrahydro-1-isopropyl-4-oxo~
imidazol-2-ylidene)-3-(3-thienyl)urea, 1-(tetrahydro-1-ethyl-4-oxo-lH-imida~ol-2-ylidene)-3-(2-thienyl)urea, 1-(4-chloro-2-furanyl)-3-(tetrahydro-1-methyl-4-oxo-lH-imidazol-2-ylidene)urea, 1-(5-carbomethoxy-2-thienyl)-3-tetrahydro-1-methyl-4-oxo-lH-imidazol-2-ylidene)urea, l-(tetrahydro 1-methyl-4-oxo-lH-imi-dazol-2-ylidene)-3(2-trifluoromethyl-4-furanyl)urea, 1-(4-pentafluoroethyl-2-furanyl)-3-(tetrahydro-1-n-propyl-4-oxo-lH-imi dazol-2-ylidene)urea, and 1-(5-aminocarboxyl-2-thienyl)-3-(tetrahydro-l-ethyl-4-oxo-lH-imidazol-2-ylidene)urea can be prepared by the process of Examine XVIII by using the equiva-lent amount of the appropriate l-alkyl-2-iminoimidazolidin~
4-one and the appropriate substituted thienyl or furanyl isocyanate as reactants.
The foll~wing Examples XXIV to XXVII further illustrate the present invention:
EXAMPLE XXIV
1-(3-Bromo-2-thienyl)-3-(tetrahydro-1-methyl-4-ox~--1-H-imidazol-2-ylidene) urea To a stirred suspension of 0.8 g (7.1 mM) of creatinine in 10 ml of anhydrous DMF was added a solution of 1.12 9 (5.5 mM) of 3-bromo~2-thienyl isocyanate in 5 ml of toluene. The resulting mixture was heated at 65C for 5 hrs.(hours), cooled, and poured into a mixture of 200 ml water and 25 ml toluene. The precipitate was collected and recrystallized from ethyl acetate to give 0.36 9 of the above urea as a tan colored solid, m.p. 192-193C. (dec.) Anal. calcd. for CgHgBrN4O2S: C, 34.08; H, 2.86; N, 17.66. Found: C, 33.95; H, 2.86; N, 17.59 EX.~MPLE XXV
1-(2-Chloro-4-thienyl)-3-~tetrahydro-1-methyl-4-oxo-lH-imidazol-2-ylidene) urea To a stirred suspension of 2.5 g (22.5 mM) of creatinine in 30 ml of anhydrous DMF was added a solution of 2.87 g (18 mM) of 2-chloro-~-thienyl isocyanate in 20 mls toluene. The resulting mixture was heated at 80C for 3.5 hrs., cooled, and poured into a mixture of 250 ml of water and 5Q ml toluene. The precipitate was collected and recrystallized from ethyl acetate to give 1.5 9 of the above urea as a tan solid, m.p. lg8-200C.
Anal. calcd. for CgHgN4Cl O~S: C, 39.64; H, 3.33; N, 20.54. Found: C, 39.55; H, 3.33; N, 20.70 ()0 EXAMPLE XXVI
1-(5-Chloro-2-thienyl)-3-(tetrahydro-1-methyl -4-oxo-lH-imidazol-2-ylidene) urea To a stirred suspension of 2.5 g (22.5 mM) of creatinine in 30 ml of anhydrous DMF was added a solution of 2.87 9 (18 mM) of 5-chloro-2-thienyl isocyanate in 15 ml of toluene. The resulting mixture was heated at 80C for 3.5 hrs., cooled, and poured into a mixture of 250 ml of water and 50 ml of toluene. The precipitate was c~llected and recrystallized from ethyl acetate to give 1.5 g o the above urea as a tan solid, m.p. 204-205C.
Anal. calcd. for C9HgN4Cl O2S: C, 39.64; H, 3.33; N, 20.54. Found: C, 3g.56; H, 3.45; N, 20.31 EXAMPLE XXVII
1~-2-Nitro-4-thienyl)-3-(tetrahydro-1-methyl 4-oxo-lH-imidazol-2-ylidene) urea To a stirred suspension of 1.4 9 ~12.5 mM) of creatinine in 40 ml of anhydrous DMF was added a solution of 1.7 9 (10 mM) of 2-nitro-4-thienyl isocyanate in 20 ml of toluene. The resulting mixture was heated at 90C for 5 hrs., cooled and poured into a mixture of 250 ml water and 50 ml toluener The precipitate was collected, washed with toluene, and recrystallized from acetone to give 0.5 9 of the above urea as a bright yellow solid, m.p. 221-222C. (dec.).
Anal. calcd. for Cg~gN504S C, 38.16; H, 3.20; N, 24.72. Found: C, 38.04; H, .3.39; N, 24.68 As indicated above, the compounds of the present invention are considered to be useful in the treatment of anxiety in living animal bodies particularly mammals.
The general class of compounds known as the benzodia-zepines is widely prescribed ~or the treatment of anxiety.
These compounds are excellent anxiolytic agents, but do have associated with them a number of ancillary activities such as sedation, muscle relaxation, anti-convulsant and hypnotic properties. Since the benzodiazepines are central nervous system depressants, they also potentiate the depressant effects of alcohol and other ~epressants such as the barbiturates;
consequently, patients using the benzodiazepines must be warned against mixing excessive doses of these compounds with alcohol and of the additive effects of sedative drugs. In the animal laboratory the Geller-Seifter Conflict test and the Shock-Induced Suppression of Drinking (SSD) test are considered good laboratory models for human anxiety. The sedative and muscle relaxant component of the benzodiazepines can be correlated with a general central nervous system (CNS) battery screen which includes the Eorced motor activity (FMA) test (to measure neuromuscular impairment) and several anti-convulsant tests (strychnine, metrazol, electroshock) which gave an indication of muscle relaxant activity. Therefore, any anxiolytic agent (as determined by the Geller-Seifter or SSD tests) can also be tested for potential sedative and muscle relaxant side-effects by using the CNS battery. Obviously, anxiolytic agents which have good activity in the Geller-Seifter or SSD tests and a low degree of sedative and muscle relaxant effects as measured by the CNS battery would be the compounds which are desired. In standard laboratory tests the compounds of the present invention, in general, as described herein demonstrate their ability to fulfill this goal, i.e., anxiolytic activity with little or no sedative action.
()0 Among the tests conducted to demonstrate the anxiolytic activity of the present compounds was the Shoclc-Induced Suppression of Drinking (Rats~ (SSD) Test which was carried out as follows:
Male rats in the weight range of 250 to 280 grams are water-deprived for 48 hours and food-deprived for 24 hours before testing. The rats are orally intubated (5 ml/kg) with the test compound (based on mg/kg body weight). The vehicle control group of rats is also intubated by mouth. A positive control group of rats is also orally administered a control dose of 18 mg/kg of chlordiazepoxide. Randomization is utilized in dosing. The rats are returned to the cage for one hour. Sixty minutes after drug administration, the rat is quietly removed from its cage and the hind feet wiped with a 10% solution of EEG electrode cream. The rat is placed on the floor in the chamber facing the licking tube. The animal is allowed 5 minutes to make 20 licking responses and receive the first shock (0.5 mA). If this does not occur, the animal is removed and eliminated from the study. If 20 licking responses are mad~, the animal is permitted an additional 3 minutes during which time each 20th lick is paired with a 0.5 mA
shock. This period is automatically started, counted, and terminate2. The number of licks and shocks are recorded. The activity of the compound tested is evaluated by comparing the mean shocks of the group dosed with the test compound to both the mean shocks of the vehicle and positive control groups.
The higher the number of shocks received the higher the anti-conflict or anti-anxiety activity the compound has.
In general, testing of the compounds of the present invention in rats in the above described SSD test indicates that the effectiYe anxiolytic dosage of the subject compounds represented by formulas (I~ and (II) in living animals, when administered orally, is from about 5 mg/kg to 200 mg~kg body weight with a more preferred range being from about 7 mg/kg to 100 mg/kg body weight.
Z6~)0 The compound of Example XV, which is a preferred compound, exhibited about the same level of ac~ivity in the above described SSD test when administered at 25 mg/kg body weight as chlordiazopoxide when administered at 18 mg/kg body weight. The compound of Example XVI, another preferred compound, when dosed at 12.5 mg/kg body weight in the SSD test demonstrated about the same level of activity as chlordiazopoxide administered at 18 mg/kg.
Based on the activities of the present heterocyclic tetrahydro-l-alkyl-4-oxo-iH-imidazol-2-ylidene urea and carbamate compounds of Formula tI) and (II) above demonstrated in standard animal tests and a comparison of these with the activities of presently known anxiolytic agents in the same tests, it is concluded that the pharmaceutical compositions of this invention may, in general, be administered to man for the treatment of anxiety at an oral dose of between about 5 mg and 500 mg of active ingredient, the composition being administered 1 to 4 times a day. A more preferred oral dosage for man is considered to be from about 5 mg to 250 mg of active ingredient 1 to 4 times a dayO It will, however, be appreciated that the amount of the pre~ent heterocyclic tetrahydro-l-alkyl-4-oxo-lH-imidazol-2-ylidene urea and carbamate compounds administered will vary depending on the degree of anxiety to be dealt with and the compound used.
Some of the subject compounds tested were also found to block acid secretion under the standard laboratory test procedure -the pylor is ligated rat (Shay Rat, WSR). Under the test utilized, five (5~ rats each weighing about 170 grams are dosed with each compound to be tested at a dose of 50 milligrams per kilogram body weight~ 59.5 milligrams of each drug to be tested is dispersed in 7 milliliters of an aqueous solution con-taining 0.5% weight/volume of hydroxypropylmethylcellulose and 0.1% weight/volume of TWEEN 80 polyoxyethylene(20)sorbitan mono-oleate. One milliliter of this resulting dispersion containing a compound to be tested is given intraduodenally to each of ()0 five (S) rats to be tested at the time of surgery. The rats are anesthetized with 37.5 milligrams per kilogram body weight of Brevital (methohexital sodium) given by interperitoneal injection. An incision about one inch long is made in the center of the abdomen of the rat going caudal from the base of tbe sternum. The incision is made with a scalpel in mid-line through to the body cavity. The duodenum is pulled through the open wound until the pyloric area is out. Then a nylon tie is placed under the antral stomach just above the pylorus and pulled tight to create a stricture. The intestines are then replaced in the body cavity and the wound closed with a wound clip~er followed by a liberal painting with collodion. After a 4 hour period each rat is sacrificed by cervical dislocation and the stomach was pulled out by the esophagus gripped by a hemostat. The stomach is then cut away from the intestine and membranes from the other end of the stomach and the stomach is cut open along the greater curviture while holding above a funnel positioned above a graduated centrifuged tube to collect the content of the stomach. The material is centrifuged at top speed for B to 12 minutes and an aliquot portion is titrated to determine the acid concentration and total acid output. A
control of five rats not dosed with a drug but given the vehicle is run with each group of rats compounds tested.
Results are reported in percent inhibition versus the controls.
The compounds of Examples I, XV and XVII when tested according to the above described procedure exhibited very significant acid anti-secretory activity. The compounds of Examples III and IV did not exhibit significant activity at this dosage; however, it is considered that they are active at a higher dosage. In general, based on test results it is considered that the effective acid blocking dosage of the compounds of this invention when administered orally is from about 10 mg/kg to 200 mg/kg body weight preferably from 10 mg/kg to 100 mg/kg body weight.
ll;ZZ~OO
As the compounds within the scope of this invention are effective upon oral administration, they can be compounded into any suitable oral dosage form, such as in tablet, capsule, syrup, elixir, suspension or other solid or liquid forms that can be prepared by procedure well known in the art. Thus, the subject novel compounds can be mixed with a suitable diluent, such as lactose or kaolin, and encapsulated, or they can be combined with suitable binding agents and expanding agents and compressed into tablets. In addition, a liquid pharmaceutical may be obtained by dissolving, dispersing, or suspending novel compounds of this invention with a suitable flavored liquid.
The present compounds are also considered active upon parenteral and rectal administration.
Examples of formulations for preparing tablets, capsules, liquids, parenterals, and suppositories containing the compounds of the present invention are described below.
Obviously, it will be recognized by one skilled in the present art that they following formulations represent only one method of preparing such pharmaceutical compositions and obviously the size of the tablet or capsule or the strength of the dosage form may be suitably varied in order to satisfy the particular re~uirements, such as dosage level indicated. For example, each dosage unit may conveniently contain from about 1 milli-gram to about 50 milligrams of the active ingredient admixed with a diluent amount of a pharmaceutically acc~ptable carrier. Any of the well known suitable pharmaceutical carriers can be used to prepare acceptable dosage forms so as to provide an effective amount or therapeutically effective amount of the compound to be administered.
0~
Suspension Containing 50 mg per 5 cc of l-(Tetrahydro-l-methyl-4-oxo-lH-imidazol-2-ylidene)-3-(2-thienyl) urea l-(Tetrahydro-l-methyl-4-oxo-lH-imidazol-2-ylidene)-3-(2-thienyl) urea 10.0 grams Tragacanth 25 gr~ms Syrup Cherry 60 ml Distilled Water, qOs. 1000 ml Hydrate the tragacenth with sufficient water to form a smooth paste and to this add the l-(Tetrahydro-l-methyl-4-oxo-lH-imidaæol-2-ylidene)-3-(2-thienyl)urea. Then add the syrup of cherry and distilled water to make 1000 ml.
Capsule Containing 25 mg of 1-(3-pyridinyl)-3-tetrahydro-1-m~thyl-4-oxo-lH-imidazol-2-ylidene) urea 1-(3-pyridinyl)-3-tetra-hydro-l-methyl-4-oxo-lH-imidazol-2-ylidene) urea 25 mg Powdered Lactose 350 mg D.T.D. Capsules No. 1000 Mix the ingredients so as to evenly distribute the active ingredient throughout the lactose. Pack the powder into a No. 1 empty gelatin capsule.
Tablet Containing 50 mg of 1-(6-methyl-2-pyridinyl)-3-tetrahydro-1-methyl-4-oxo-lH-imidazol-2-ylidene) urea 1-(6-methyl-2-pyridinyl)-3-tetrahydro-1-methyl-4-oxo-lH-imidazol-2-ylidene) urea 50 grams ll;~Z~()O
Starch 160 grams Powdered Lactose 160 grams Talc 20 grams Weight of Granulation390 grams Combine all ingredients, mix, and then compress into slugs. The slugs should then be ground to form granules that will pass through a 14 to 16 mesh screen. The granules may then be recompressed into 1000 tablets using a suitable com-pression mold to form tablets, each weighing 345 mg.
Injectable Containing 40 mg of l-(Tetrahydro-l-methyl-4-oxo-lH-imidazol-2-ylidene)~3-(3-thienyl) urea l-(Tetrahydro-l-methyl-4 -oxo-lH-imidazol-2-ylidene)-3-~3-thienyl) urea 40.0 grams Chlorobutanol 3.0 grams Propylene Glycol 40.0 grams Water for Injection, q.s. 1000.0 m' Combine the above ingredients, clarify by filtration, fill into vials, seal, and autoclave.
The resul~ing mixture was heated at 75C. for 3 hrs., cooled, and poured into 200 ml of water. The precipitate was collec-ted, washed with ethanol and ether, and air-dried. The solid was dissolved in 250 ml hot acetone, treated with charcoal, filtered, and the filtrate diluted with water (250 ml). The resulting precipitate was collected, washed with acetone and then ether. Air-drying gave 2.3 9 of the above urea as a buff powder, m.p. 192-193C~ (dec.).
Anal. calcd. for CgHgBrN4O2S: C, 34.08; H, 2.86; N, 17.66. Found C, 33.94; H, 3.04; N, 17.30 EXAMPLE XXI
1-(5-Methoxy-2-thienyl)-3-(tetrahydro-1-methyl-4-oxo-lH-imidazol-2-ylidene) urea To a stirred suspension of 3.0 9 (26 mM) of creati-nine in 25 ml of anhydrous DMF was added a solution of 4.1 9 (26 T~M) of 5-methoxy-2-thienyl isocyanate in 20 ml of toluene.
The resulting mixture was heated at 65C. for 4.5 hrs., cooled, and poured into 200 ml of water. The mixture was extracted with ethyl acetate, and the combined extracts dried (MgSO4) and concentrated. The residue was recrystallized from e~hyl acetate and then ethanol. Final purification was accomplished by chromatography over silica gel ~ethyl acetate as eluant), decolorizing the product with charcoal, concentra-tion and recrystallization froTn acetone-hexane to give 0.23 9 of the above urea as a light brown solid, m.p. 180-182C.
~dec.).
i()V
Anal- calcd- for ClOH12N43S C, 44-78; H~ 4-51;
20.88. Found: C, 44.71; H, 4.67; N, 20.88 EXAMPLE XXII
1-(2-Furanyl-3-(tetrahydro-1-methyl-4-oxo-lH-imidazol-2-ylidene) urea To a stirred mixture of 6.9 g (60 mM) of creatinine in 100 ml of anhydrous ~MF was added a solution of 6.5 g (60 mM) of 2-furanyl isocyanate in 75 ml of toluene. After stirring the mixture 1 hr. at 25C. and then 1 hr. at 55C., the solvents were emoved in vacuo and the residue taken up in ethyl acetate and washed with water. The solvent was removed and the residue chromatographed over silica gel using ether-ethyl acetate (4:1) as the eluant. The fractions containing the product were combined and concentrated to leave 1.1 g of the above urea as an off-white solid, m.p.
173-175C. (dec.) Anal. calcd. for CgHloN4O3: C, 48.65; H, 4.53: N, 25.21. Found: C, 48.54; H, 4072; N, 24.92 EX~MPLE XXIII
1-(3-Furanyl-3-(tetrahydro-1-methyl-4-oxo-lH-imidazol-2-ylidene) urea To a stirred mixture of 18.3 9 (162 mM) of creatinine in 120 ml of anhydrous DMF was added a solution of 17.2 g (162 mM) of 3-furanyl isocyanate in 80 ml of toluene. After stirring the mixture for 3 hrs. at 65C., the mixture was partially concentrated under vacuum and the residue poured into 1200 ml of water. The resulting precipitate was collected, washed with water and recrystallized from e~hyl acetate. The solid was then chroma~ographed over silica gel using ethyl acetate as the eluant and the fractions containing the product were concentrated and the residue recrystallized from toluene to give 0.5 9 of the above urea as a tan solid, m.p.
179-181C. (dec.).
Anal. calcd. for CgHloN4O3: C, 48.65; H, 4.53; N, 25.21. Found: C, 48.85; H, 4.68 N, 25.17 To further illustrate the preparation of the com-pounds of the present invention l-(tetrahydro-l-methyl-4-oxo-lH-imidazol-2-ylidene)-3-(6-trifluoromethyl-2-pyridinyl)urea, 1-(4-chloro-6-methyl-2-pyridinyl)-3-(tetrahydro-1-ethyl-4-oxo-lH-imidazol-2-ylidene)urea, 1-(5-carboxyl-2-pyridinyl)-3-(tetra-hydro-l-isopropyl-4-oxo-lH-imidazol-2-ylidene)urea, and 1-(2-pyridinyl)-3-(tetrahydro-1-pentyl-4-oxo-1~-imidazol-2-yli-dene)urea can be prepared by the method of Example VI by using the equivalent amount of the appropriate phenyl ester of tetrahydro-l-alkyl-4-oxo-lH-imidazol-2-ylidene carbamic acid and the appropriate substituted aminopyridine as reactants.
1-(3-methyl-2-furanyl)-3-(tetrahydro-1-ethyl-4-oxo-lH-m imidazol-2-ylidene)urea, 1-(tetrahydro-1-isopropyl-4-oxo~
imidazol-2-ylidene)-3-(3-thienyl)urea, 1-(tetrahydro-1-ethyl-4-oxo-lH-imida~ol-2-ylidene)-3-(2-thienyl)urea, 1-(4-chloro-2-furanyl)-3-(tetrahydro-1-methyl-4-oxo-lH-imidazol-2-ylidene)urea, 1-(5-carbomethoxy-2-thienyl)-3-tetrahydro-1-methyl-4-oxo-lH-imidazol-2-ylidene)urea, l-(tetrahydro 1-methyl-4-oxo-lH-imi-dazol-2-ylidene)-3(2-trifluoromethyl-4-furanyl)urea, 1-(4-pentafluoroethyl-2-furanyl)-3-(tetrahydro-1-n-propyl-4-oxo-lH-imi dazol-2-ylidene)urea, and 1-(5-aminocarboxyl-2-thienyl)-3-(tetrahydro-l-ethyl-4-oxo-lH-imidazol-2-ylidene)urea can be prepared by the process of Examine XVIII by using the equiva-lent amount of the appropriate l-alkyl-2-iminoimidazolidin~
4-one and the appropriate substituted thienyl or furanyl isocyanate as reactants.
The foll~wing Examples XXIV to XXVII further illustrate the present invention:
EXAMPLE XXIV
1-(3-Bromo-2-thienyl)-3-(tetrahydro-1-methyl-4-ox~--1-H-imidazol-2-ylidene) urea To a stirred suspension of 0.8 g (7.1 mM) of creatinine in 10 ml of anhydrous DMF was added a solution of 1.12 9 (5.5 mM) of 3-bromo~2-thienyl isocyanate in 5 ml of toluene. The resulting mixture was heated at 65C for 5 hrs.(hours), cooled, and poured into a mixture of 200 ml water and 25 ml toluene. The precipitate was collected and recrystallized from ethyl acetate to give 0.36 9 of the above urea as a tan colored solid, m.p. 192-193C. (dec.) Anal. calcd. for CgHgBrN4O2S: C, 34.08; H, 2.86; N, 17.66. Found: C, 33.95; H, 2.86; N, 17.59 EX.~MPLE XXV
1-(2-Chloro-4-thienyl)-3-~tetrahydro-1-methyl-4-oxo-lH-imidazol-2-ylidene) urea To a stirred suspension of 2.5 g (22.5 mM) of creatinine in 30 ml of anhydrous DMF was added a solution of 2.87 g (18 mM) of 2-chloro-~-thienyl isocyanate in 20 mls toluene. The resulting mixture was heated at 80C for 3.5 hrs., cooled, and poured into a mixture of 250 ml of water and 5Q ml toluene. The precipitate was collected and recrystallized from ethyl acetate to give 1.5 9 of the above urea as a tan solid, m.p. lg8-200C.
Anal. calcd. for CgHgN4Cl O~S: C, 39.64; H, 3.33; N, 20.54. Found: C, 39.55; H, 3.33; N, 20.70 ()0 EXAMPLE XXVI
1-(5-Chloro-2-thienyl)-3-(tetrahydro-1-methyl -4-oxo-lH-imidazol-2-ylidene) urea To a stirred suspension of 2.5 g (22.5 mM) of creatinine in 30 ml of anhydrous DMF was added a solution of 2.87 9 (18 mM) of 5-chloro-2-thienyl isocyanate in 15 ml of toluene. The resulting mixture was heated at 80C for 3.5 hrs., cooled, and poured into a mixture of 250 ml of water and 50 ml of toluene. The precipitate was c~llected and recrystallized from ethyl acetate to give 1.5 g o the above urea as a tan solid, m.p. 204-205C.
Anal. calcd. for C9HgN4Cl O2S: C, 39.64; H, 3.33; N, 20.54. Found: C, 3g.56; H, 3.45; N, 20.31 EXAMPLE XXVII
1~-2-Nitro-4-thienyl)-3-(tetrahydro-1-methyl 4-oxo-lH-imidazol-2-ylidene) urea To a stirred suspension of 1.4 9 ~12.5 mM) of creatinine in 40 ml of anhydrous DMF was added a solution of 1.7 9 (10 mM) of 2-nitro-4-thienyl isocyanate in 20 ml of toluene. The resulting mixture was heated at 90C for 5 hrs., cooled and poured into a mixture of 250 ml water and 50 ml toluener The precipitate was collected, washed with toluene, and recrystallized from acetone to give 0.5 9 of the above urea as a bright yellow solid, m.p. 221-222C. (dec.).
Anal. calcd. for Cg~gN504S C, 38.16; H, 3.20; N, 24.72. Found: C, 38.04; H, .3.39; N, 24.68 As indicated above, the compounds of the present invention are considered to be useful in the treatment of anxiety in living animal bodies particularly mammals.
The general class of compounds known as the benzodia-zepines is widely prescribed ~or the treatment of anxiety.
These compounds are excellent anxiolytic agents, but do have associated with them a number of ancillary activities such as sedation, muscle relaxation, anti-convulsant and hypnotic properties. Since the benzodiazepines are central nervous system depressants, they also potentiate the depressant effects of alcohol and other ~epressants such as the barbiturates;
consequently, patients using the benzodiazepines must be warned against mixing excessive doses of these compounds with alcohol and of the additive effects of sedative drugs. In the animal laboratory the Geller-Seifter Conflict test and the Shock-Induced Suppression of Drinking (SSD) test are considered good laboratory models for human anxiety. The sedative and muscle relaxant component of the benzodiazepines can be correlated with a general central nervous system (CNS) battery screen which includes the Eorced motor activity (FMA) test (to measure neuromuscular impairment) and several anti-convulsant tests (strychnine, metrazol, electroshock) which gave an indication of muscle relaxant activity. Therefore, any anxiolytic agent (as determined by the Geller-Seifter or SSD tests) can also be tested for potential sedative and muscle relaxant side-effects by using the CNS battery. Obviously, anxiolytic agents which have good activity in the Geller-Seifter or SSD tests and a low degree of sedative and muscle relaxant effects as measured by the CNS battery would be the compounds which are desired. In standard laboratory tests the compounds of the present invention, in general, as described herein demonstrate their ability to fulfill this goal, i.e., anxiolytic activity with little or no sedative action.
()0 Among the tests conducted to demonstrate the anxiolytic activity of the present compounds was the Shoclc-Induced Suppression of Drinking (Rats~ (SSD) Test which was carried out as follows:
Male rats in the weight range of 250 to 280 grams are water-deprived for 48 hours and food-deprived for 24 hours before testing. The rats are orally intubated (5 ml/kg) with the test compound (based on mg/kg body weight). The vehicle control group of rats is also intubated by mouth. A positive control group of rats is also orally administered a control dose of 18 mg/kg of chlordiazepoxide. Randomization is utilized in dosing. The rats are returned to the cage for one hour. Sixty minutes after drug administration, the rat is quietly removed from its cage and the hind feet wiped with a 10% solution of EEG electrode cream. The rat is placed on the floor in the chamber facing the licking tube. The animal is allowed 5 minutes to make 20 licking responses and receive the first shock (0.5 mA). If this does not occur, the animal is removed and eliminated from the study. If 20 licking responses are mad~, the animal is permitted an additional 3 minutes during which time each 20th lick is paired with a 0.5 mA
shock. This period is automatically started, counted, and terminate2. The number of licks and shocks are recorded. The activity of the compound tested is evaluated by comparing the mean shocks of the group dosed with the test compound to both the mean shocks of the vehicle and positive control groups.
The higher the number of shocks received the higher the anti-conflict or anti-anxiety activity the compound has.
In general, testing of the compounds of the present invention in rats in the above described SSD test indicates that the effectiYe anxiolytic dosage of the subject compounds represented by formulas (I~ and (II) in living animals, when administered orally, is from about 5 mg/kg to 200 mg~kg body weight with a more preferred range being from about 7 mg/kg to 100 mg/kg body weight.
Z6~)0 The compound of Example XV, which is a preferred compound, exhibited about the same level of ac~ivity in the above described SSD test when administered at 25 mg/kg body weight as chlordiazopoxide when administered at 18 mg/kg body weight. The compound of Example XVI, another preferred compound, when dosed at 12.5 mg/kg body weight in the SSD test demonstrated about the same level of activity as chlordiazopoxide administered at 18 mg/kg.
Based on the activities of the present heterocyclic tetrahydro-l-alkyl-4-oxo-iH-imidazol-2-ylidene urea and carbamate compounds of Formula tI) and (II) above demonstrated in standard animal tests and a comparison of these with the activities of presently known anxiolytic agents in the same tests, it is concluded that the pharmaceutical compositions of this invention may, in general, be administered to man for the treatment of anxiety at an oral dose of between about 5 mg and 500 mg of active ingredient, the composition being administered 1 to 4 times a day. A more preferred oral dosage for man is considered to be from about 5 mg to 250 mg of active ingredient 1 to 4 times a dayO It will, however, be appreciated that the amount of the pre~ent heterocyclic tetrahydro-l-alkyl-4-oxo-lH-imidazol-2-ylidene urea and carbamate compounds administered will vary depending on the degree of anxiety to be dealt with and the compound used.
Some of the subject compounds tested were also found to block acid secretion under the standard laboratory test procedure -the pylor is ligated rat (Shay Rat, WSR). Under the test utilized, five (5~ rats each weighing about 170 grams are dosed with each compound to be tested at a dose of 50 milligrams per kilogram body weight~ 59.5 milligrams of each drug to be tested is dispersed in 7 milliliters of an aqueous solution con-taining 0.5% weight/volume of hydroxypropylmethylcellulose and 0.1% weight/volume of TWEEN 80 polyoxyethylene(20)sorbitan mono-oleate. One milliliter of this resulting dispersion containing a compound to be tested is given intraduodenally to each of ()0 five (S) rats to be tested at the time of surgery. The rats are anesthetized with 37.5 milligrams per kilogram body weight of Brevital (methohexital sodium) given by interperitoneal injection. An incision about one inch long is made in the center of the abdomen of the rat going caudal from the base of tbe sternum. The incision is made with a scalpel in mid-line through to the body cavity. The duodenum is pulled through the open wound until the pyloric area is out. Then a nylon tie is placed under the antral stomach just above the pylorus and pulled tight to create a stricture. The intestines are then replaced in the body cavity and the wound closed with a wound clip~er followed by a liberal painting with collodion. After a 4 hour period each rat is sacrificed by cervical dislocation and the stomach was pulled out by the esophagus gripped by a hemostat. The stomach is then cut away from the intestine and membranes from the other end of the stomach and the stomach is cut open along the greater curviture while holding above a funnel positioned above a graduated centrifuged tube to collect the content of the stomach. The material is centrifuged at top speed for B to 12 minutes and an aliquot portion is titrated to determine the acid concentration and total acid output. A
control of five rats not dosed with a drug but given the vehicle is run with each group of rats compounds tested.
Results are reported in percent inhibition versus the controls.
The compounds of Examples I, XV and XVII when tested according to the above described procedure exhibited very significant acid anti-secretory activity. The compounds of Examples III and IV did not exhibit significant activity at this dosage; however, it is considered that they are active at a higher dosage. In general, based on test results it is considered that the effective acid blocking dosage of the compounds of this invention when administered orally is from about 10 mg/kg to 200 mg/kg body weight preferably from 10 mg/kg to 100 mg/kg body weight.
ll;ZZ~OO
As the compounds within the scope of this invention are effective upon oral administration, they can be compounded into any suitable oral dosage form, such as in tablet, capsule, syrup, elixir, suspension or other solid or liquid forms that can be prepared by procedure well known in the art. Thus, the subject novel compounds can be mixed with a suitable diluent, such as lactose or kaolin, and encapsulated, or they can be combined with suitable binding agents and expanding agents and compressed into tablets. In addition, a liquid pharmaceutical may be obtained by dissolving, dispersing, or suspending novel compounds of this invention with a suitable flavored liquid.
The present compounds are also considered active upon parenteral and rectal administration.
Examples of formulations for preparing tablets, capsules, liquids, parenterals, and suppositories containing the compounds of the present invention are described below.
Obviously, it will be recognized by one skilled in the present art that they following formulations represent only one method of preparing such pharmaceutical compositions and obviously the size of the tablet or capsule or the strength of the dosage form may be suitably varied in order to satisfy the particular re~uirements, such as dosage level indicated. For example, each dosage unit may conveniently contain from about 1 milli-gram to about 50 milligrams of the active ingredient admixed with a diluent amount of a pharmaceutically acc~ptable carrier. Any of the well known suitable pharmaceutical carriers can be used to prepare acceptable dosage forms so as to provide an effective amount or therapeutically effective amount of the compound to be administered.
0~
Suspension Containing 50 mg per 5 cc of l-(Tetrahydro-l-methyl-4-oxo-lH-imidazol-2-ylidene)-3-(2-thienyl) urea l-(Tetrahydro-l-methyl-4-oxo-lH-imidazol-2-ylidene)-3-(2-thienyl) urea 10.0 grams Tragacanth 25 gr~ms Syrup Cherry 60 ml Distilled Water, qOs. 1000 ml Hydrate the tragacenth with sufficient water to form a smooth paste and to this add the l-(Tetrahydro-l-methyl-4-oxo-lH-imidaæol-2-ylidene)-3-(2-thienyl)urea. Then add the syrup of cherry and distilled water to make 1000 ml.
Capsule Containing 25 mg of 1-(3-pyridinyl)-3-tetrahydro-1-m~thyl-4-oxo-lH-imidazol-2-ylidene) urea 1-(3-pyridinyl)-3-tetra-hydro-l-methyl-4-oxo-lH-imidazol-2-ylidene) urea 25 mg Powdered Lactose 350 mg D.T.D. Capsules No. 1000 Mix the ingredients so as to evenly distribute the active ingredient throughout the lactose. Pack the powder into a No. 1 empty gelatin capsule.
Tablet Containing 50 mg of 1-(6-methyl-2-pyridinyl)-3-tetrahydro-1-methyl-4-oxo-lH-imidazol-2-ylidene) urea 1-(6-methyl-2-pyridinyl)-3-tetrahydro-1-methyl-4-oxo-lH-imidazol-2-ylidene) urea 50 grams ll;~Z~()O
Starch 160 grams Powdered Lactose 160 grams Talc 20 grams Weight of Granulation390 grams Combine all ingredients, mix, and then compress into slugs. The slugs should then be ground to form granules that will pass through a 14 to 16 mesh screen. The granules may then be recompressed into 1000 tablets using a suitable com-pression mold to form tablets, each weighing 345 mg.
Injectable Containing 40 mg of l-(Tetrahydro-l-methyl-4-oxo-lH-imidazol-2-ylidene)~3-(3-thienyl) urea l-(Tetrahydro-l-methyl-4 -oxo-lH-imidazol-2-ylidene)-3-~3-thienyl) urea 40.0 grams Chlorobutanol 3.0 grams Propylene Glycol 40.0 grams Water for Injection, q.s. 1000.0 m' Combine the above ingredients, clarify by filtration, fill into vials, seal, and autoclave.
Claims (20)
1. A process of reacting a compound of the formula wherein R is an alkyl radical containing 1 to 8 carbon atoms, with an isocyanate of the formula OCN - Z
wherein Z is a pyridinyl, thienyl or furanyl radical which may be substituted with one to three radicals independently selected from hydroxy, alkoxy containing 1 to 8 carbon atoms, alkyl of 1 to 8 carbon atoms, halogen, nitro, NR1R2, CONR1R2, haloalkyl containing 1 to 8 carbon atoms and COOR1 where R1 and R2 are independently hydrogen or an alkyl radical containing 1 to 8 carbon atoms.
wherein Z is a pyridinyl, thienyl or furanyl radical which may be substituted with one to three radicals independently selected from hydroxy, alkoxy containing 1 to 8 carbon atoms, alkyl of 1 to 8 carbon atoms, halogen, nitro, NR1R2, CONR1R2, haloalkyl containing 1 to 8 carbon atoms and COOR1 where R1 and R2 are independently hydrogen or an alkyl radical containing 1 to 8 carbon atoms.
2. A compound of the formula wherein R is an alkyl radical containing 1 to 8 carbon atoms;
and Z is a pyridinyl, thienyl or furanyl radical which may be substituted with one to three radicals independently selected from hydroxy, alkoxy containing 1 to 8 carbon atoms, alkyl of 1 to 8 carbon atoms, halogen, nitro, NR1R2, CONR1R2, haloalkyl containing 1 to 8 carbon atoms and COOR1 where R1 and R2 are independently hydrogen or an alkyl radical containing 1 to 8 carbon atoms; or a pharmaceutically acceptable acid-addition salt thereof, when produced by the process of Claim 1.
and Z is a pyridinyl, thienyl or furanyl radical which may be substituted with one to three radicals independently selected from hydroxy, alkoxy containing 1 to 8 carbon atoms, alkyl of 1 to 8 carbon atoms, halogen, nitro, NR1R2, CONR1R2, haloalkyl containing 1 to 8 carbon atoms and COOR1 where R1 and R2 are independently hydrogen or an alkyl radical containing 1 to 8 carbon atoms; or a pharmaceutically acceptable acid-addition salt thereof, when produced by the process of Claim 1.
3. A process of reacting a compound of the formula wherein R is an alkyl radical containing 1 to 8 carbon atoms, with an isocyanate of the formula OCN-Z
wherein Z is 2-chloro-4-thienyl.
wherein Z is 2-chloro-4-thienyl.
4. A compound of the formula wherein R is an alkyl radical containing 1 to 8 carbon atoms;
and Z is 2-chloro-4-thienyl; or a pharmaceutically acceptable acid-addition salt thereof, when produced by the process of Claim 3.
and Z is 2-chloro-4-thienyl; or a pharmaceutically acceptable acid-addition salt thereof, when produced by the process of Claim 3.
5. A process of reacting a compound of the formula wherein R is an alkyl radical containing 1 to 8 carbon atoms, with an isocyanate of the formula OCN-Z
wherein Z is 2-pyridinyl
wherein Z is 2-pyridinyl
6. A compound of the formula wherein R is an alkyl radical containing 1 to 8 carbon atoms;
and Z is 2-pyridinyl; or a pharmaceutically acceptable acid-addition salt thereof, when produced by the process of Claim 5.
and Z is 2-pyridinyl; or a pharmaceutically acceptable acid-addition salt thereof, when produced by the process of Claim 5.
7. A process of reacting a compound of the formula wherein R is an alkyl radical containing 1 to 8 carbon atoms, with an isocyanate of the formula OCN-Z
wherein Z is 3-pyridinyl.
wherein Z is 3-pyridinyl.
8. A compound of the formula wherein R is an alkyl radical containing 1 to 8 carbon atoms;
and Z is 3-pyridinyl; or a pharmaceutically acceptable acid-addition salt thereof, when produced by the process of Claim 7.
and Z is 3-pyridinyl; or a pharmaceutically acceptable acid-addition salt thereof, when produced by the process of Claim 7.
9. A process of reacting a compound of the formula wherein R is an alkyl radical containing 1 to 8 carbon atoms, with an isocyanate of the formula OCN-Z
wherein Z is 4-pyridinyl.
wherein Z is 4-pyridinyl.
10. A compound of the formula wherein R is an alkyl radical containing 1 to 8 carbon atoms;
and Z is 4-pyridinyl; or a pharmaceutically acceptable acid-addition salt thereof, when produced by the process of Claim 9.
and Z is 4-pyridinyl; or a pharmaceutically acceptable acid-addition salt thereof, when produced by the process of Claim 9.
11. A process of reacting a compound of the formula wherein R is an alkyl radical containing 1 to 8 carbon atoms, with an isocyanate of the formula OCN-Z
wherein Z is 6-methyl-2-pyridinyl.
wherein Z is 6-methyl-2-pyridinyl.
12, A compound of the formula wherein R is an alkyl radical containing 1 to 8 carbon atoms;
and Z is 6-methyl-2-pyridinyl; or a pharmaceutically acceptable acid-addition salt thereof, when produced by the process of Claim 11.
and Z is 6-methyl-2-pyridinyl; or a pharmaceutically acceptable acid-addition salt thereof, when produced by the process of Claim 11.
13. A process of reacting a compound of the formula wherein R is an alkyl radical containing 1 to 8 carbon atoms, with an isocyanate of the formula OCN-Z
wherein Z is 2-thienyl.
wherein Z is 2-thienyl.
14. A compound of the formula wherein R is an alkyl radical containing 1 to 8 carbon atoms;
and Z is 2-thienyl; or a pharmaceutically acceptable acid-addition salt thereof, when produced by the process of Claim 13,
and Z is 2-thienyl; or a pharmaceutically acceptable acid-addition salt thereof, when produced by the process of Claim 13,
15. A process of reacting a compound of the formula wherein R is an alkyl radical containing 1 to 8 carbon atoms, with an isocyanate of the formula OCN-Z
wherein Z is 3-thienyl.
wherein Z is 3-thienyl.
16. A compound of the formula wherein R is an alkyl radical containing 1 to 8 carbon atoms;
and Z is 3-thienyl; or a pharmaceutically acceptable acid-addition salt thereof, when produced by the process of Claim 15.
and Z is 3-thienyl; or a pharmaceutically acceptable acid-addition salt thereof, when produced by the process of Claim 15.
17. A process of reacting a compound of the formula wherein R is an alkyl radical containing 1 to 8 carbon atoms, with an isocyanate of the formula OCN-Z
wherein Z is 2-furanyl.
wherein Z is 2-furanyl.
18. A compound of the formula wherein R is an alkyl radical containing 1 to 8 carbon atoms;
and Z is 2-furanyl; or a pharmaceutically acceptable acid-addition salt thereof, when produced by the process of Claim 17.
and Z is 2-furanyl; or a pharmaceutically acceptable acid-addition salt thereof, when produced by the process of Claim 17.
19. A process of reacting a compound of the formula wherein R is an alkyl radical containing 1 to 8 carbon atoms, with an isocyanate of the formula OCN-Z
wherein Z is 3-furanyl.
wherein Z is 3-furanyl.
20. A compound of the formula wherein R is an alkyl radical containing 1 to 8 carbon atoms;
and Z is 3-furanyl; or a pharmaceutically acceptable acid-addition salt thereof, when produced by the process of Claim 19.
and Z is 3-furanyl; or a pharmaceutically acceptable acid-addition salt thereof, when produced by the process of Claim 19.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US06/004,675 US4230713A (en) | 1979-01-19 | 1979-01-19 | Heterocyclic tetrahydro-1-alkyl-4-oxo-1H-imidazol-2-ylidene urea and phenyl esters of tetrahydro-1-alkyl-4-oxo-1H-imidazol-2-ylidene carbamic acid compounds |
| US4,675 | 1979-01-19 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1122600A true CA1122600A (en) | 1982-04-27 |
Family
ID=21711951
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA341,498A Expired CA1122600A (en) | 1979-01-19 | 1979-12-07 | Heterocyclic tetrahydro-1-alkyl-4-oxo-1h-imidazol-2- ylidene urea and phenyl esters of tetrahydro-1-alkyl-4-oxo-1h imidazol-2-ylidene carbamic acid compounds |
Country Status (6)
| Country | Link |
|---|---|
| US (1) | US4230713A (en) |
| EP (1) | EP0013817B1 (en) |
| JP (1) | JPS55100380A (en) |
| AT (1) | ATE3769T1 (en) |
| CA (1) | CA1122600A (en) |
| DE (1) | DE2965701D1 (en) |
Families Citing this family (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4472583A (en) * | 1980-02-05 | 1984-09-18 | The Dow Chemical Company | 4-Isothiocyanato-2,6-bis-(trifluoromethyl)pyridine |
| DE3674054D1 (en) * | 1985-04-26 | 1990-10-18 | Hoffmann La Roche | 1,3-DISUBSTITUTED IMIDAZOLI SALTS. |
| US4657922A (en) * | 1985-05-24 | 1987-04-14 | Mcneilab, Inc. | Anxiolytic 4,5-dihydro-4-oxo-1H-imidazol-2-yl urea derivatives |
| DE59805833D1 (en) | 1997-07-22 | 2002-11-07 | Basf Coatings Ag | COATING AGENTS AND METHOD FOR THE PRODUCTION THEREOF |
| US20030220646A1 (en) * | 2002-05-23 | 2003-11-27 | Thelen Sarah L. | Method and apparatus for reducing femoral fractures |
| NZ569607A (en) * | 2005-12-20 | 2011-06-30 | Astrazeneca Ab | Substituted cinnoline derivatives as GABBA-receptor modulators and method for their synthesis |
| US7465795B2 (en) * | 2005-12-20 | 2008-12-16 | Astrazeneca Ab | Compounds and uses thereof |
| AR067028A1 (en) * | 2007-06-19 | 2009-09-30 | Astrazeneca Ab | COMPOUNDS AND USES OF THE SAME 849 |
| JP2021529834A (en) * | 2018-07-03 | 2021-11-04 | アイエフエム デュー インコーポレイテッド | Compounds and compositions for treating conditions associated with STING activity |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3983135A (en) * | 1974-09-23 | 1976-09-28 | Mcneil Laboratories, Incorporated | 4-Oxo-2-imidazolidinylidene ureas |
-
1979
- 1979-01-19 US US06/004,675 patent/US4230713A/en not_active Expired - Lifetime
- 1979-12-07 CA CA341,498A patent/CA1122600A/en not_active Expired
- 1979-12-17 EP EP79302921A patent/EP0013817B1/en not_active Expired
- 1979-12-17 AT AT79302921T patent/ATE3769T1/en not_active IP Right Cessation
- 1979-12-17 DE DE7979302921T patent/DE2965701D1/en not_active Expired
-
1980
- 1980-01-18 JP JP375680A patent/JPS55100380A/en active Pending
Also Published As
| Publication number | Publication date |
|---|---|
| EP0013817A1 (en) | 1980-08-06 |
| ATE3769T1 (en) | 1983-06-15 |
| JPS55100380A (en) | 1980-07-31 |
| DE2965701D1 (en) | 1983-07-21 |
| EP0013817B1 (en) | 1983-06-15 |
| US4230713A (en) | 1980-10-28 |
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