CA1239150A - Anti-atherosclerotic trisubstituted ureas - Google Patents
Anti-atherosclerotic trisubstituted ureasInfo
- Publication number
- CA1239150A CA1239150A CA000459032A CA459032A CA1239150A CA 1239150 A CA1239150 A CA 1239150A CA 000459032 A CA000459032 A CA 000459032A CA 459032 A CA459032 A CA 459032A CA 1239150 A CA1239150 A CA 1239150A
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- Prior art keywords
- urea
- chloro
- phenyl
- compound
- hydrogen
- Prior art date
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-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C275/00—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
- C07C275/28—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
- C07C275/30—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton being further substituted by halogen atoms, or by nitro or nitroso groups
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/06—Antihyperlipidemics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
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- General Health & Medical Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Heart & Thoracic Surgery (AREA)
- Vascular Medicine (AREA)
- Cardiology (AREA)
- Urology & Nephrology (AREA)
- Diabetes (AREA)
- Hematology (AREA)
- Obesity (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
ABSTRACT
Substituted urea derivatives, and processes for their preparation of the general formula are described, in which A is a halo-substituted phenyl group; n is 1 to 5;
R1 and R2 are each hydrogen or lower alkyl; and Z is hydrogen, lower alkoxy, halo, or the group (CH2)m-CR3R4-CH3, in which m is 0 to 5; and R3 and R4 are hydrogen or lower alkyl, with the proviso that R1, R2, R3 and R4 cannot all be hydrogen. These compounds find use in heating atherosclerosis, in reducing the cholesterol content of arterial walls, in treating hyperlipidemia, and in inhibiting atherosclerotic lesion development in mammals. The compounds are generally administered combined with a suitable pharmaceutically acceptable carrier, and passes the practical advantage that they may be administered orally as well as by injection.
Substituted urea derivatives, and processes for their preparation of the general formula are described, in which A is a halo-substituted phenyl group; n is 1 to 5;
R1 and R2 are each hydrogen or lower alkyl; and Z is hydrogen, lower alkoxy, halo, or the group (CH2)m-CR3R4-CH3, in which m is 0 to 5; and R3 and R4 are hydrogen or lower alkyl, with the proviso that R1, R2, R3 and R4 cannot all be hydrogen. These compounds find use in heating atherosclerosis, in reducing the cholesterol content of arterial walls, in treating hyperlipidemia, and in inhibiting atherosclerotic lesion development in mammals. The compounds are generally administered combined with a suitable pharmaceutically acceptable carrier, and passes the practical advantage that they may be administered orally as well as by injection.
Description
Ed I
ANTI ATHEROSCLEROTIC UREAS AND THERESA
This invention relates to novel ureas containing alkyd groups which are branched at the penultimate carbon of the alkyd chain. The invention further relates to the chemical syntheses of these ureas, pharmaceutical combo-sessions containing these ureas, and the use of these urea sin the treatment of atherosclerosis.
The novel ureas of this invention are repro-sensed by the following formula:
O R
If I .
A--NHCN--( SHEA ) nCCH3 I
Z
wherein, A is 4-(trifluoromethyl)phenyl, 4-chloro-2-methylphenyl, 4-chloro-2,5-dimethylphenyl, 4-chloro-2,6-dimethyl-phenol, 2,4-difluorophenyl, 2,4,6-trichlorophenyl, or
ANTI ATHEROSCLEROTIC UREAS AND THERESA
This invention relates to novel ureas containing alkyd groups which are branched at the penultimate carbon of the alkyd chain. The invention further relates to the chemical syntheses of these ureas, pharmaceutical combo-sessions containing these ureas, and the use of these urea sin the treatment of atherosclerosis.
The novel ureas of this invention are repro-sensed by the following formula:
O R
If I .
A--NHCN--( SHEA ) nCCH3 I
Z
wherein, A is 4-(trifluoromethyl)phenyl, 4-chloro-2-methylphenyl, 4-chloro-2,5-dimethylphenyl, 4-chloro-2,6-dimethyl-phenol, 2,4-difluorophenyl, 2,4,6-trichlorophenyl, or
2,4,6-trifluorophenyl;
n is a positive integer from one to five;
.
;,. I .
Al and R2 are independent of one another and are hydrogen or (Cl-C4)alkyl; and Z is hydrogen, (Cl-Cs)alkoxy, halo or the group - ( SHEA )m<CH3 in which m is an integer from 0 to 5 and R3 and R4 are independent of one another and are hydrogen or (Cl-C4)alkyl; with the proviso that Al, R2, R3, and R4 cannot all be hydrogen.
Preferred compounds of this invention are the following ureas:
1-(3,3-Dimethylbutyl)-1-[[4-(n-butyl)phenyl]methyllo (4-chloro-2,6-dimethylphenyl)urea, 1-(3,3-Dimethylbutyl)-1-[[4-(2,2-dimethylpropyl)phHoneywell]-methyl]-3-(4-chloro-2,6-dimethylphenyl)urea, 1-(3,3-Dimethylbutyl)-1-[[4-(n-butyl)phenyl]methyllo (2,4,6-trifluorophenyl)urea, 1-[[4-(2,2-Dimethylpropyl)phenyl]m~thyl]-l-(n-hepttwill)-
n is a positive integer from one to five;
.
;,. I .
Al and R2 are independent of one another and are hydrogen or (Cl-C4)alkyl; and Z is hydrogen, (Cl-Cs)alkoxy, halo or the group - ( SHEA )m<CH3 in which m is an integer from 0 to 5 and R3 and R4 are independent of one another and are hydrogen or (Cl-C4)alkyl; with the proviso that Al, R2, R3, and R4 cannot all be hydrogen.
Preferred compounds of this invention are the following ureas:
1-(3,3-Dimethylbutyl)-1-[[4-(n-butyl)phenyl]methyllo (4-chloro-2,6-dimethylphenyl)urea, 1-(3,3-Dimethylbutyl)-1-[[4-(2,2-dimethylpropyl)phHoneywell]-methyl]-3-(4-chloro-2,6-dimethylphenyl)urea, 1-(3,3-Dimethylbutyl)-1-[[4-(n-butyl)phenyl]methyllo (2,4,6-trifluorophenyl)urea, 1-[[4-(2,2-Dimethylpropyl)phenyl]m~thyl]-l-(n-hepttwill)-
3-(2,4-difluorophenyl)urea, 1-[[4-(2,2-Dimethylpropyl~phenyl]methyl]-l-(n-hepttwill)-3-(4-chloro-2,6-dimethylphenyl)urea, 1-[[4-(2,2-Dimethylpropyl)phenyl]methyl]-l-(n-hepttwill)-3-(2,4,6-trifluorophenyl)urea, 30 1-[[4-(n-Butyl)phenyl]methyl]-1-(3,3-dimethylbutyllo (4-chloro-2,6-dimethylphenyl)urea.
This invention also relates to a method of treating atherosclerosis in mammals, reduction of the cholesterol content of the arterial walls in mammals, the treatment of hyperlipidemia in mammals and the inhibition of atherosclerotic lesion development in mammals which comprises administering to said mammals an effective amount of a compound as defined above.
.
The compounds of this invention may be prepared by reacting an arylisocyanate of the formula:
A-N=C=O
wherein A is as defined above, with a secondary amine of the formula:
Al 10 Ho SHEA ) nCCH3 wherein n, Al, R2, and Z are as defined above.
A second process for the preparation of compounds of this invention involves reacting a compound of the formula: -A-NHC-B
wherein A is as defined above and B is selected from the group consisting of halogen, (Cl-C4)alkoxy, (Cl-C4)alkyl-trio, phonics, 4-chlorophenoxy, and 4-nitrophenoxy; with a secondary amine of the formula:
... .
Al Ho SHEA ) n~CH3 wherein n, Al, R2, and Z are as defined above.
Many of the novel ureas of this invention are prepared by reacting arylisocyanates with secondary amine.
These reactions may be performed in aprotic solvents such as hexane, deathly ether, Tulane, tetrahydrofuran, and the like at temperatures from room temperature or below up to the boiling point of the solvent used. The ureas are isolated by filtration or by evaporating the solvent and they may be purified by recrystallization, absorption chromatography, or distillation under reduced pressure.
An example of this process is the reaction of deflower-phenylisocyanate with 4-(2,2-dimethylpropyl)-N-(n-heptyl)-benzenemethanamine to yield 3-t2,4-difluorophenyl)-1-[~4-(2,2-dimethylpropyl)phenyl]methyl]-1-(n-heptyl)ureea.
Certain of the novel ureas of this invention are prepared by reacting arylamines with activated derivatives of carbonic acid such as phosgene or phenol chloroform ate to yield an intermediate, for instance, an arylcarbamyl chloride. This intermediate is then reacted with a second-cry amine to yield the urea. The preparation of this intermediate is conducted in an aprotic solvent such as Tulane or zillion at temperatures from about room tempera-lure up to the boiling point of the solvent in the presence of a base, for example, N,N-dimethylaniline.
The intermediate is then reacted with a secondary amine in an aprotic solvent such as Tulane at tempera lures from room temperature or below up to the boiling :, - .
, : . . : .
.
I P
point of the solvent. An example of this process is the reaction of 4-chloro-2,6-dimethylbenzeneamine with phenol chloroform ate to yield phenol (4-chloro-2,6-dimethylphen-yl)carbamate as an intermediate. This intermediate is 5 then reacted with a secondary amine such as Dow-methylpropyl)-N-(n-heptyl)benzenemethanamine to yield a urea, in this case 3-(4-chloro-2,6-dimethylphenyl)-1-[[4-(2,2-dimethylpropyl)phenyl]methyl~-1-(n-heptylLowry.
The ureas of the present invention are obtained as crystalline solids or distillable liquids. They are characterized by distinct melting or boiling points and unique spectra. They are appreciably soluble in organic solvents but generally less soluble in water.
The properties and utility of the compounds of this invention will be illustrated in conjunction with the specific tables shown below.
The compounds of the present invention were assayed for two types of biological activity related to their potential use as anti atherosclerotic agents. Come pounds were tested in vitro for their ability to inhibit the enzyme fatty azalea CoA:cholesterol azalea transfers (ACT) and in viva for hypolipidemic activity as measured by their ability to inhibit lipid absorption in rats. The compounds were tested for their ability to inhibit ACT
according to the following procedure:
Rat adrenals were homogenized in 0.2 M monobasic potassium phosphate buffer, pi 7.4, and centrifuged at Luke times gravity for 15 minutes at 5C. The super-Nat ant, containing the microsomal fraction, served as the source of the cholesterol-esterifying enzyme, fatty azalea 30 CoA:cholesterol azalea transfers (ACT). A mixture come prosing 50 parts of adrenal supernatant, 10 parts of albumin (BRA) (50 mg/ml), 3 parts of test compound, and 500 parts of buffer was preincubated at 37C for 10 mint vies. After treatment with 20 parts of 14C-palmitoyl 35 CoA(final concentration 20 EM) the mixture was incubated at 37C for 10 minutes. A control mixture, omitting the I
test compound, was prepared and treated in the same manner.
The lipids from the incubation mixture were extracted into an organic solvent and separated by thin-layer chromatog-rough. The cholesterol ester fraction was counted in a 5 scintillation counter. This procedure is a modification of that described by Hashimoto, et at , Life Science, 12 (Part II), 1-12 (1973). The results of this test at van-out concentrations of each compound were then used to obtain the Issue for that compound. The Issue is defined as lo that concentration of a compound which produces 50~ inhibit lion of the enzyme. Results of these tests are shown in Table I.
TABLE I
_ I .
Compound ISSUE EM
_ _ _ 3-(2,4-Difluorophenyl)-1-[[4-(2,2-dimethyl- 1.32 propyl)phenyl]methyl]-l-(n-heptyl)urea 3-(4-Chloro-2,6-dimethylphenyl)-1-[[4-(2,2- 0.31 dimethylpropyl)phenyl]methyl]-l-(n~heptyl)urea 1-[[4-(2,2-Dimethylpropyl)phenyl]methyl]-l-(n-0.122 heptyl)-3-(2,4,6-trifluorophenyl)urea 1-(3,3-Dimethylbutyl)-1-[4-(n-butyl)benzyl]-3- 1.29 (4-chloro-2-methylphenyl)urea 25 1-(3,3-Dimethylbutyl)-1-[4-(n-butoxy)benzyl]-3-1.666 (4-chloro-2-methylphenyl)urea 1-(3,3-Dimethylbutyl)-1-[4-(n-butoxy)benzyl]-3-0.554 (2,4,6-tirchlorophenyl)urea 1-(3,3-Dimethylbutyl)-1-[4-(n-butoxy)benzyl]-3-10..00 (2,4-difluorophenyl)urea 1-(3,3-Dimethylbutyl)-1-~4-(n-butyl)benzyl]-3- 1.50 (2,4-difluorophenyl)urea .
.
.
I
TABLE I (continued) Compound ISSUE EM
1-(3,3-Dimethylbutyl)-1-[4-(n-butyl)benzyl~-3-0.633 (2,4,6-trichlorophenyl)urea 1-(5,5-Dimethylhexyl)-1-[4-(n-butyl)benzyll-3-0.755 (4-chloro-2-methylphenyl)urea .1-(5,5-Dimethylhexyl)-1-[4-(n-butyl)benzyl]-3-1.200 (2,4-difluorophenyl)urea 1-(5,5-Dimethylhexyl)-1-~4-(n-butyl)benzyl]-3-0.066 (2,4,6-trichlorophenyl)urea 1-(3,3-Dimethylbutyl)-1-~4-chlorobenzyl)-3-(4-0.899 chloro-2-methylphenyl)urea 1-(3,3-Dimethylbutyl)-l-benzyl-3-(2,4-difluoro-3.114 phenyl)urea 1-(3,3-Dimethylbutyl)-1-(4-chlorobenzyl)-3- 3.54 (2,4-aifluorophenyl)urea 1-(3,3-Dimethylbutyl)-1-(4-chlorobenzyl)-3- 0.51 (2,4,6-trichlorophenyl)urea 1-(3,3-Dimethylbutyl)-1-[4-(n-butyl)benzyl]-3-3.044 (4-trifluoromethylphenyl)urea 1-(3,3-Dimethylbutyl)-1-(4-chlorobenzyl)-3- 2.61 (4-trifluoromethylphenyl)urea 1-(3,3-Dimethylbutyl)-1-[4-(2,2-dimethyl- 1.00 propyl)benzyl]-3-(2,4-difluorophenyl)urea 1-(3,3-Dimethylbutyl)-1-[4-(2,2-dimethyl- 0.95 propyl)benzyl]-3-(4-chloro-2-methylphenyl)urea 1-(3,3-Dimethylbutyl)-1-[4-(2,2-dimethyl- 1.02 propyl)benzyl]-3-(2l4,6-trichlorophenyl)urea 3Q 1-(3,3-Dimethylbutyl)-1-[4-(n-butyl~benzyl]-3-0.700 (4-chloro-2,6-dimethylphenyl)urea 1-~3,3-Dimethylbutyl)-1-(4-chlorobenzyl)-3-(4-n . 65 chloro-2,6-dimethylphenyl)urea .. . .
TABLE I continued) I Compound ISSUE EM
5 1-(3,3-Dimethylbutyl)~ 4-(2,2-dimethyl- 0.84 propyl)benzyl]-3-(4-chloro-2,6-dimethylphenyl)-urea 1-(3,3-Dimethylbutyl)-l-benzyl-3-(4-chloro-2- 1.16 methylphenyl)urea l-t3,3-Dimethylbutyl)-l-(benzyl)-3-(4-chloro- 2.60 2,5-dimethylphenyl)urea 1-~(4-Butylphenyl)methyl]-1 [3,3-dimethyl- 0.11 butyl]-3-[2,4,6-trifluorophenyl~urea l-Benzyl-l-[3,3-dimethylbutyl]-3-[2,4,6-tri- 0.91 fluorophenyl]urea l-[3,3-Dimethylbutyl]-1-[4-(2,2-dimethyl- 0.05 propyl)phenyl]-3-[2,4,6-trifluorophenyl]urea Inhibition of cholesterol absorption was deter-mined by feeding male Sprague-Dawley rats, weighing 150-170 g, a 1% cholesterol colic acid diet for 2 weeks.
The diet also contained compounds being tested at a dose of 0.03% of the diet. Control rats were fed the same diet without any compound. At the end of the test, the rats were sacrificed by decapitation. Blood is collected, centrifuged at 1.5 kg times gravity for 10 minutes at 4C; and the serum is then analyzed for cholesterol and triglycerides enzymatic ally by the method of Tinder, P., 3Q Analyst, 77, 321 (1952) on a Centrifichem 400 analyzer.
Livers are removed, a 0.4 g sample is taken from the eon-ton of the large lobe, and the sample is subjected to saponification using 25% saturated potassium hydroxide in ethanol. The resulting neutral strolls are extracted with petroleum ether and extract analyzed for cholesterol.
The effectiveness of the compound in inhibiting chores-.. .
. . .
r twirl absorption is measured by the lowering of either serum cholesterol to liver cholesterol relative to the values for control rats.
Compounds which produced statistically signify-cant inhibition of cholesterol absorption are considered to be active. Liver stroll LO and serum stroll (SO) values are expressed as a percentage of control values.
The results of this test on typical compounds of this invention appear in Table II.
TABLE II
Compound LO SO
._ .
3-(2,4-Difluorophenyl)-1-[[4-(2,2-dimethyl- 2424 propyl)phenyl]methyl]-l-(n-heptyl)urea 3-(4-Chloro-2,6-dimethylphenyl)-1-[[4-(2,2- 1731 dimethylpropyl)phenyl]methyl]-l-(n-heptyl)urea 1-[[4-(2,2-Dimethylpropyl)phenyl]methyl]-1- 1421 (n-heptyl)-3-(2,4,6-trifluorophenyl)urea 1-(3,3-Dimethylbutyl)-1-[4-(n-butyl)benzyl]-3- 1346 (4-chloro-2-methylphenyl)urea 1-(3,3-Dimethylbutyl)-1-[4-(n-butoxy)benzyl]- 2261 3-(4-chloro-2-methylphenyl)urea 1-(3,3-Dimethylbutyl)-1-[4-(n-butoxy)benzyl]- 2052 3-(2,4,6-trichlorophenyl)urea 1-(3,3-Dimethylbutyl)-1-[4-(n-butoxy)benzyl]- 3242 3-(2,4-difluorophenyl)urea 1-(3,3-Dimethylbutyl)-1-[4-(n-butyl)benzyl]-3- 3039 (2,4-difluorophenyl)urea 1-(3,3-Dimethylbutyl)-1-[4-(n-butyl)benzyl]-3- 1337 (2,4,6-trichlorophenyl)urea 1-(5,5-Dime~hylhexyl)-1-[4-(n-butyl)benzyl]-3- 3442 (4-chloro-2-methylphenyl)urea (5~5-Dimethylhexyl)-l-[4-(n-butyl)benzyl]-3- 5~59 (2,4-difluorophenyl)urea _ .
TALE II (continued) Compound LO SO
1-(5,5-Dimethylhexyl)-1-[4-(n-butyl)benzyl~-3- 32 45 (2,4,6-trichlorophenyl)urea 1-(3,3-Dimethylbutyl)-1-(4-chlorobenzyl)-3- 60 50 (4-chloro-2-methylphenyl)urea 1-(3,3-Dimethylbutyl)-l-benzyl-3-(2,4-di- 70 71 fluorophenyl)urea I 1-(3,3-Dimethylbutyl)-1-(4-chlorobenzyl)-3- 69 43 (2,4-difluorophenyl)urea 1-(3,3-Dimethylbutyl)-1-(4-chlorobenzyl)-3- 70 85 (4-tri~luoromethylphenyl)urea 1-(3,3-Dimethylbutyl)-1-[4-(2,2-dimethyl- 19 35 propyl)benzyl]-3-(2,4-difluorophenyl)urea . 1-(3,3-Dimethylbutyl)-1-[4-(2,2-dimethyl- 20 51 propyl)benzyl]-3-(4-chloro-2-methylphenyl)urea 1-(3,3-Dimethylbutyl)-1-[4-(2,2-dimethyl- 15 32 propyl)benzyl]-3-(2,4,6-trichlorophenyl)urea 1-(3,3-Dimethylbutyl)-1-[4-(n-butyl)benzyl]-3- 12 28 (4-chloro-2,6-dimethylphenyl)urea 1-(3,3-Dimethylbutyl)-1-(4-chlorobenzyl)-3- 25 46 (4-chloro-2,6-dimethylphenyl)urea 1-(3,3-Dimethylbutyl)-1-[4-(2,2-dimethyl- 11 31 propyl)benzyl]-3-(4-chloro-2,6-dimethyl.-phenyl)urea 1-(3,3-Dimethylbutyl)-l-benzyl-3-(4-chloro-2- 51 64 methylphenyl)urea 1-(3,3-Dimethylbutyl)-l-(benzyl)-3-(4-chloro- ¦ 30 55 35 2,5-dimethylphenyl)urea 1-(3,3-Dimethylbutyl)~ 4-(n-butyl)benzyl]-3- 12 28 (4-chloro-2,5-dimethylphenyl)urea _ I
TABLE II (continued) Compound LO
1-(3,3-Dimethylbutyl)-1-[4-(2,2-dimethyl- 15 29 propyl)benzyl]-3-(4-chloro-2,5-dimethyl-phenyl)urea 1-[(4-Butylphenyl)methyl]-1-[3,3-dimethyl- 28 24 butyl]-3-[2,4,6-trifluorophenyl]urea l-Benzyl-1-[3,3-dimethylbutyl~-3-[2,4,6-tri- 77 57 fluorophenyl]urea 1-[3,3-Dimethylbutyl]-1-[4-(2,2-dimethyl- 17 19 propyl)phenyl]-3-[2,4,6-trifluorophenyl]urea 1-[(4-Isopropylphenyl)methyl]-1-(3-methyl- 37 butyl)-3-(2,4-difluorophenyl)urea 1-[(4-Isopropylphenyl)methyl]-1-(3-methyl- 23 butyl)-3-(4-chloro-2,6-dimethyiphenyl)urea 1-[(4-Isopropylphenyl)methyl]-1-(3-methyl- 35 butyl)-3-(2,4,6-trifluorophenyl)urea When the compounds are employed for the above utility, they may be combined with one or more forum-ceutically acceptable carriers, e.g., solvents, delineates, and the like, and may be administered orally in such forms as tablets, capsules, dispersible powders, granules, or suspensions containing, for example, from about 0.5 to 5%
of suspending agent, syrups containing, for example, prom about 10 to 50% of sugar, and elixirs containing, for example, from about 20 to 50% ethanol, and the like, or parenterally in the form of sterile injectable solutions or suspensions containing from about 0.5 to 5% suspending agent in an isotonic medium. These pharmaceutical prepay rations ma contain, for example, from about 0.5 up to about 90% or the active ingredient in combination with the carrier, more usually between 5 and 60~ by weight.
The anti atherosclerotic effective dosage of active ingredient employed may vary depending on the par-titular compound employed, the mode of administration, and the severity of the condition being treated. However, in general, satisfactory results are obtained when the come pounds of the invention are administered at a daily dosage of from about 2 my to about 500 mg/kg of animal body weight, preferably given in divided doses two to four times a day, or in sustained release form. For most large mammals, the total daily dosage is from about 100 my to about 5,000 my, preferably from about 100 my to 2,000 my.
Dosage forms suitable for internal use comprise from about 25 to 500 my of the active compound in intimate admixture with a solid or liquid pharmaceutically acceptable car-nor. This dosage regimen may be adjusted to provide the optimal therapeutic response. For example, several divided doses may be administered daily or the dose may be proper-tonally reduced as indicated by the exigencies of the therapeutic situation. A decided practical advantage is that these active compounds may be administered orally as well as by intravenous, intramuscular, or subcutaneous routes if necessary. Solid carriers include starch, fag-lose, dicalcium phosphate, microcrystalline cellulose sucrose and kaolin, while liquid carriers include sterile water, polyethylene glycols, non-ionic surfactants, and edible oils such as corn, peanut, and sesame oils, as are appropriate to the nature of the active ingredient and the particular form of administration desired. Adjutants customarily employed in the preparation of pharmaceutical compositions may be advantageously included, such as flay vowing agents, coloring agents, preserving agents, and antioxidant, e.g., vitamin En, ascorbic acid, BUT, and 30 BRA.
The preferred pharmaceutical compositions from the stand-point of ease of preparation and administration are solid compositions, particularly tablets and hard-filled or liquid-filled capsules. Oral administration of the compounds is preferred.
,, These active compounds may also be administered parenterally or intraperitoneally. Solutions or suspend sons of these active compounds as a free base or forum-ecologically acceptable salt can be prepared in water suit-5 ably mixed with a surfactant such as hydroxypropylcellu-lose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of micro-10 organisms.
The pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In all cases, the form must be sterile and must be fluid to the extent that easy syringability exists. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of micro-organisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g., glycerol, propylene glycol, and liquid polyethylene glycol), suitable mixtures thereof, and vegetable oils.
The preparation and properties of the compounds of this invention will be described in greater detail in conjunction with the specific examples shown below.
Example 1 3-(2,4-Difluorophenyl)-l-[[4-(2,2-dimethylpropYl) phenyl]methyl]-l-(n-heptyl)urea pa A solution of 6.73 g of 4-(neopentyl)benzoic acid and 13.0 ml of thinly chloride in 40 ml of dichloro-methane was heated at reflex for 4 hours. The reaction mixture was cooled and the solvent was evaporated in vacua. The residue was dissolved in dichloromethane and evaporated again. This step was repeated a second time and 4-(neopentyl)benzoyl chloride was obtained as a brown O i 1 .
I.
I
The preceding product was dissolved in 40 ml of dichloromethane and added with stirring to a cold solution of 4.04 g of Natalie amine and 9.8 ml of triethylamine in 60 ml of dichloromethane. The resulting mixture was stirred at room temperature for 16 hours. The mixture was diluted with water and two layers were separated. The organic layer was washed in succession with two 30 ml portions of 3 N hydrochloric acid. The solution was dried over an hydrous magnesium sulfate and filtered. The lit-irate was evaporated in vacua to yield 13.0 g of a Griswold. The solid was purified by preparative high pressure liquid chromatography on silica gel using ethyl acetate:-hexane (1:9) as the fluent. Several fractions were come brined and evaporated in vacua to yield 8.0 g of 4-(2,2-dimethylpropyl)-N-(n-heptyl)benzamide as a beige solid, my 58-60C.
A mixture of 7.5 g (0.026 moles) of the pro-ceding aside and 20 ml (0.052 moles) of Nitride T [sodium dihydrobis(2-methoxyethoxy)aluminate (70~ solution in Tulane)] in 80 ml of Tulane was reflexed for 4 hours, then cooled to room temperature. The complex was deco-posed by adding drops, 40 ml of 2.5 N sodium hydroxide with stirring during 30 minutes. The organic layer was separated and washed with brine, dried over an hydrous magnesium sulfate and filtered. The filtrate was vapor-axed to dryness in vacua to yield a yellow oil. Kugelrohr distillation (125C/0.15 mm of mercury) gave 5.45 g (90%) of4-(2,2-dimethylpropyl)-N-(n-heptyl)benzenemethanammine as a colorless liquid.
To a solution of 1.10 g (0.004 moles) of the preceding amine in 15 ml of hexane was added with stirring a solution of 0.62 g (0.004 moles) of 2,4-difluorophenyl-isocyanate in 15 ml of hexane. The resulting mixture was stirred at room temperature for 16 hours. The solvent was 35 evaporated in vacua to yield a colorless oil. Kugelrohr distillation (140-155C/0.15 mm of mercury) gave 1.44 g (84%) of the desired product as a colorless oil.
Example 2 3-(4-Chloro-2,6-dimethYlPhenyl)-1-~4-(2,2-dimethyll-propvl)phenyl]methyl]-l-(n-heptyl)urea To a mixture of 300 g t2.48 moles) of Dow-methyl aniline, 2.4 liters of dichloromethane and 24 ml of ethanol cooled at 5C in an ice bath was added an hydrous hydrogen chloride gas over a one hour period maintaining the reaction mixture temperature at 4-11C. Chlorine gas was passed through the mixture for approximately 2 hours 10 while the temperature was maintained at 5-10C during which time approximately 217 g of chlorine was introduced.
The reaction mixture was examined several times by thin layer chromatography using 10:1 ethyl acetate:hexane as a solvent system. Upon completion of the reaction, the 15 mixture was purged with argon gas, then allowed to stand at room temperature for 16 hours.
The mixture was cooled to 2C and filtered. The precipitate was washed with 250 ml of dichloromethane, followed by 1.5 liters of ether, and then air dried to 20 yield 371 g of 4-chloro-2,6-dimethylbenzeneamine mender-chloride.
To a suspension of the preceding monohydrochlor-ire 371 g (1.93 moles) in 1.5 liters of deathly ether maintained at 12-17C in an ice bath was added one liter 25 of 2 M sodium acetate solution over a 2~3 minute period with vigorous stirring. The mixture was stirred for 30 minutes then allowed to stand to separate 2 layers. The organic layer was washed in succession with one liter volumes of water, saturated sodium bicarbonate, then water again. The organic solution was dried over an hydrous sodium sulfate and filtered. Evaporation gave 288 g of solid. This solid was recrystallized from 800 ml of petrol Lomb ether and gave 229 g of 4~chloro-2l6-dimethylbenzene-amine as colorless crystals, my 47-50C.
To a cold solution of 2.47 g (0.0163 moles) of the above amine and 2.4 ml (0.0189 moles) of N,N-dimethyl-aniline in 80 ml of Tulane was added drops a solution . , of 2.56 g (0.0163 moles) of phenylchloroformate in 20 ml of Tulane. The resulting mixture was stirred at room temperature for 90 minutes then diluted with water. The organic layer was separated and washed with two 40 ml portions of 3 N hydrochloric acid, then with brine. The organic solution was dried over an hydrous magnesium sulfate and filtered. The filtrate was evaporated in vacua to yield a white solid. The solid was recrystallized from ethyl acetate:hexane to yield 3.8 g of phenyl(4-chloro-10 2,6-dimethylphenyl)carbamate as a white solid, my 158-160C.
A mixture of 1.11 g (0.004 moles) of the pro-ceding carbamate, 1.10 g (0.004 moles) of 4-(2,2-dimethyl-propyl)-N-(n-heptyl)benzenemethanamine (prepared in 15 Example 1) and 30 ml of Tulane was reflexed for 2 hours.
The solution was cooled, washed with two 30 ml portions of 1 _ sodium hydroxide, then with brine. The solution was dried over an hydrous magnesium sulfate and filtered. The filtrate was evaporated _ vacua to yield an oil. Cudgel-I roar distillation (145-155C/0.1 mm of mercury) gave 1.47 g of colorless oil which solidified on standing to yield the product of the Example as a white solid, my 111-113C.
Example 3 1-~[4-(2,2-Dimethylpropyl)phenyl]methyl]-l-(n-hepttwill)-3-(2,4,6-trifluorophenyl)urea To a cold solution of 5.3 g (0~0359 moles) of 2,4,6-trifluoroaniline and 5.6 ml (5.4 g, 0.044 moles) of N,N-dimethylaniline in 70 ml of Tulane was added drops a solution of 5.63 g (0.0359 moles) of phenol chloroform ate 30 in 20 ml of Tulane. The resulting mixture was stirred at room temperature for 16 hours and gave a precipitate. The mixture was diluted with ethyl acetate and water. The organic layer was separated and washed with two 50 ml portions of 3 N hydrochloric acid, then with two 50 ml 35 portions of brine. The solution was dried over an hydrous magnesium sulfate and filtered. The filtrate was vapor-.
I Ed axed in vacua to yield a solid. The solid was triturated with hexane, collected by filtration, washed with hexane and dried to yield 8.38 g ~96~) of phenyl(2,4,6-trifluoro-phenyl)carbamate as a white solid, my 127-128C.
A mixture of 0.97 g ~0.004 moles) of the pro-ceding carbamate, 1.10 g (0.004 moles) of 4-(2,2-dimethyl-propyl)-N-(n-heptyl)ben~enemethanamine (prepared in Example 1) and 40 ml of Tulane was reflexed or 2 hours.
The resulting solution was cooled, washed with two 30 ml 10 portions of 1 N sodium hydroxide, then with brine. The solution was dried over an hydrous magnesium sulfate, lit-toned and evaporated in vacua and gave a light yellow oil.
Kugelrohr distillation (140-150C/0.08 mm of mercury) gave 1.5 g of colorless oil. A 900 my portion of this oil was lo redistilled (140-150C/0.160 mm of mercury) to yield 500 my of the product of the Example as a colorless oil.
The ureas shown in Table III were prepared using the methods described in Examples 1-3.
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This invention also relates to a method of treating atherosclerosis in mammals, reduction of the cholesterol content of the arterial walls in mammals, the treatment of hyperlipidemia in mammals and the inhibition of atherosclerotic lesion development in mammals which comprises administering to said mammals an effective amount of a compound as defined above.
.
The compounds of this invention may be prepared by reacting an arylisocyanate of the formula:
A-N=C=O
wherein A is as defined above, with a secondary amine of the formula:
Al 10 Ho SHEA ) nCCH3 wherein n, Al, R2, and Z are as defined above.
A second process for the preparation of compounds of this invention involves reacting a compound of the formula: -A-NHC-B
wherein A is as defined above and B is selected from the group consisting of halogen, (Cl-C4)alkoxy, (Cl-C4)alkyl-trio, phonics, 4-chlorophenoxy, and 4-nitrophenoxy; with a secondary amine of the formula:
... .
Al Ho SHEA ) n~CH3 wherein n, Al, R2, and Z are as defined above.
Many of the novel ureas of this invention are prepared by reacting arylisocyanates with secondary amine.
These reactions may be performed in aprotic solvents such as hexane, deathly ether, Tulane, tetrahydrofuran, and the like at temperatures from room temperature or below up to the boiling point of the solvent used. The ureas are isolated by filtration or by evaporating the solvent and they may be purified by recrystallization, absorption chromatography, or distillation under reduced pressure.
An example of this process is the reaction of deflower-phenylisocyanate with 4-(2,2-dimethylpropyl)-N-(n-heptyl)-benzenemethanamine to yield 3-t2,4-difluorophenyl)-1-[~4-(2,2-dimethylpropyl)phenyl]methyl]-1-(n-heptyl)ureea.
Certain of the novel ureas of this invention are prepared by reacting arylamines with activated derivatives of carbonic acid such as phosgene or phenol chloroform ate to yield an intermediate, for instance, an arylcarbamyl chloride. This intermediate is then reacted with a second-cry amine to yield the urea. The preparation of this intermediate is conducted in an aprotic solvent such as Tulane or zillion at temperatures from about room tempera-lure up to the boiling point of the solvent in the presence of a base, for example, N,N-dimethylaniline.
The intermediate is then reacted with a secondary amine in an aprotic solvent such as Tulane at tempera lures from room temperature or below up to the boiling :, - .
, : . . : .
.
I P
point of the solvent. An example of this process is the reaction of 4-chloro-2,6-dimethylbenzeneamine with phenol chloroform ate to yield phenol (4-chloro-2,6-dimethylphen-yl)carbamate as an intermediate. This intermediate is 5 then reacted with a secondary amine such as Dow-methylpropyl)-N-(n-heptyl)benzenemethanamine to yield a urea, in this case 3-(4-chloro-2,6-dimethylphenyl)-1-[[4-(2,2-dimethylpropyl)phenyl]methyl~-1-(n-heptylLowry.
The ureas of the present invention are obtained as crystalline solids or distillable liquids. They are characterized by distinct melting or boiling points and unique spectra. They are appreciably soluble in organic solvents but generally less soluble in water.
The properties and utility of the compounds of this invention will be illustrated in conjunction with the specific tables shown below.
The compounds of the present invention were assayed for two types of biological activity related to their potential use as anti atherosclerotic agents. Come pounds were tested in vitro for their ability to inhibit the enzyme fatty azalea CoA:cholesterol azalea transfers (ACT) and in viva for hypolipidemic activity as measured by their ability to inhibit lipid absorption in rats. The compounds were tested for their ability to inhibit ACT
according to the following procedure:
Rat adrenals were homogenized in 0.2 M monobasic potassium phosphate buffer, pi 7.4, and centrifuged at Luke times gravity for 15 minutes at 5C. The super-Nat ant, containing the microsomal fraction, served as the source of the cholesterol-esterifying enzyme, fatty azalea 30 CoA:cholesterol azalea transfers (ACT). A mixture come prosing 50 parts of adrenal supernatant, 10 parts of albumin (BRA) (50 mg/ml), 3 parts of test compound, and 500 parts of buffer was preincubated at 37C for 10 mint vies. After treatment with 20 parts of 14C-palmitoyl 35 CoA(final concentration 20 EM) the mixture was incubated at 37C for 10 minutes. A control mixture, omitting the I
test compound, was prepared and treated in the same manner.
The lipids from the incubation mixture were extracted into an organic solvent and separated by thin-layer chromatog-rough. The cholesterol ester fraction was counted in a 5 scintillation counter. This procedure is a modification of that described by Hashimoto, et at , Life Science, 12 (Part II), 1-12 (1973). The results of this test at van-out concentrations of each compound were then used to obtain the Issue for that compound. The Issue is defined as lo that concentration of a compound which produces 50~ inhibit lion of the enzyme. Results of these tests are shown in Table I.
TABLE I
_ I .
Compound ISSUE EM
_ _ _ 3-(2,4-Difluorophenyl)-1-[[4-(2,2-dimethyl- 1.32 propyl)phenyl]methyl]-l-(n-heptyl)urea 3-(4-Chloro-2,6-dimethylphenyl)-1-[[4-(2,2- 0.31 dimethylpropyl)phenyl]methyl]-l-(n~heptyl)urea 1-[[4-(2,2-Dimethylpropyl)phenyl]methyl]-l-(n-0.122 heptyl)-3-(2,4,6-trifluorophenyl)urea 1-(3,3-Dimethylbutyl)-1-[4-(n-butyl)benzyl]-3- 1.29 (4-chloro-2-methylphenyl)urea 25 1-(3,3-Dimethylbutyl)-1-[4-(n-butoxy)benzyl]-3-1.666 (4-chloro-2-methylphenyl)urea 1-(3,3-Dimethylbutyl)-1-[4-(n-butoxy)benzyl]-3-0.554 (2,4,6-tirchlorophenyl)urea 1-(3,3-Dimethylbutyl)-1-[4-(n-butoxy)benzyl]-3-10..00 (2,4-difluorophenyl)urea 1-(3,3-Dimethylbutyl)-1-~4-(n-butyl)benzyl]-3- 1.50 (2,4-difluorophenyl)urea .
.
.
I
TABLE I (continued) Compound ISSUE EM
1-(3,3-Dimethylbutyl)-1-[4-(n-butyl)benzyl~-3-0.633 (2,4,6-trichlorophenyl)urea 1-(5,5-Dimethylhexyl)-1-[4-(n-butyl)benzyll-3-0.755 (4-chloro-2-methylphenyl)urea .1-(5,5-Dimethylhexyl)-1-[4-(n-butyl)benzyl]-3-1.200 (2,4-difluorophenyl)urea 1-(5,5-Dimethylhexyl)-1-~4-(n-butyl)benzyl]-3-0.066 (2,4,6-trichlorophenyl)urea 1-(3,3-Dimethylbutyl)-1-~4-chlorobenzyl)-3-(4-0.899 chloro-2-methylphenyl)urea 1-(3,3-Dimethylbutyl)-l-benzyl-3-(2,4-difluoro-3.114 phenyl)urea 1-(3,3-Dimethylbutyl)-1-(4-chlorobenzyl)-3- 3.54 (2,4-aifluorophenyl)urea 1-(3,3-Dimethylbutyl)-1-(4-chlorobenzyl)-3- 0.51 (2,4,6-trichlorophenyl)urea 1-(3,3-Dimethylbutyl)-1-[4-(n-butyl)benzyl]-3-3.044 (4-trifluoromethylphenyl)urea 1-(3,3-Dimethylbutyl)-1-(4-chlorobenzyl)-3- 2.61 (4-trifluoromethylphenyl)urea 1-(3,3-Dimethylbutyl)-1-[4-(2,2-dimethyl- 1.00 propyl)benzyl]-3-(2,4-difluorophenyl)urea 1-(3,3-Dimethylbutyl)-1-[4-(2,2-dimethyl- 0.95 propyl)benzyl]-3-(4-chloro-2-methylphenyl)urea 1-(3,3-Dimethylbutyl)-1-[4-(2,2-dimethyl- 1.02 propyl)benzyl]-3-(2l4,6-trichlorophenyl)urea 3Q 1-(3,3-Dimethylbutyl)-1-[4-(n-butyl~benzyl]-3-0.700 (4-chloro-2,6-dimethylphenyl)urea 1-~3,3-Dimethylbutyl)-1-(4-chlorobenzyl)-3-(4-n . 65 chloro-2,6-dimethylphenyl)urea .. . .
TABLE I continued) I Compound ISSUE EM
5 1-(3,3-Dimethylbutyl)~ 4-(2,2-dimethyl- 0.84 propyl)benzyl]-3-(4-chloro-2,6-dimethylphenyl)-urea 1-(3,3-Dimethylbutyl)-l-benzyl-3-(4-chloro-2- 1.16 methylphenyl)urea l-t3,3-Dimethylbutyl)-l-(benzyl)-3-(4-chloro- 2.60 2,5-dimethylphenyl)urea 1-~(4-Butylphenyl)methyl]-1 [3,3-dimethyl- 0.11 butyl]-3-[2,4,6-trifluorophenyl~urea l-Benzyl-l-[3,3-dimethylbutyl]-3-[2,4,6-tri- 0.91 fluorophenyl]urea l-[3,3-Dimethylbutyl]-1-[4-(2,2-dimethyl- 0.05 propyl)phenyl]-3-[2,4,6-trifluorophenyl]urea Inhibition of cholesterol absorption was deter-mined by feeding male Sprague-Dawley rats, weighing 150-170 g, a 1% cholesterol colic acid diet for 2 weeks.
The diet also contained compounds being tested at a dose of 0.03% of the diet. Control rats were fed the same diet without any compound. At the end of the test, the rats were sacrificed by decapitation. Blood is collected, centrifuged at 1.5 kg times gravity for 10 minutes at 4C; and the serum is then analyzed for cholesterol and triglycerides enzymatic ally by the method of Tinder, P., 3Q Analyst, 77, 321 (1952) on a Centrifichem 400 analyzer.
Livers are removed, a 0.4 g sample is taken from the eon-ton of the large lobe, and the sample is subjected to saponification using 25% saturated potassium hydroxide in ethanol. The resulting neutral strolls are extracted with petroleum ether and extract analyzed for cholesterol.
The effectiveness of the compound in inhibiting chores-.. .
. . .
r twirl absorption is measured by the lowering of either serum cholesterol to liver cholesterol relative to the values for control rats.
Compounds which produced statistically signify-cant inhibition of cholesterol absorption are considered to be active. Liver stroll LO and serum stroll (SO) values are expressed as a percentage of control values.
The results of this test on typical compounds of this invention appear in Table II.
TABLE II
Compound LO SO
._ .
3-(2,4-Difluorophenyl)-1-[[4-(2,2-dimethyl- 2424 propyl)phenyl]methyl]-l-(n-heptyl)urea 3-(4-Chloro-2,6-dimethylphenyl)-1-[[4-(2,2- 1731 dimethylpropyl)phenyl]methyl]-l-(n-heptyl)urea 1-[[4-(2,2-Dimethylpropyl)phenyl]methyl]-1- 1421 (n-heptyl)-3-(2,4,6-trifluorophenyl)urea 1-(3,3-Dimethylbutyl)-1-[4-(n-butyl)benzyl]-3- 1346 (4-chloro-2-methylphenyl)urea 1-(3,3-Dimethylbutyl)-1-[4-(n-butoxy)benzyl]- 2261 3-(4-chloro-2-methylphenyl)urea 1-(3,3-Dimethylbutyl)-1-[4-(n-butoxy)benzyl]- 2052 3-(2,4,6-trichlorophenyl)urea 1-(3,3-Dimethylbutyl)-1-[4-(n-butoxy)benzyl]- 3242 3-(2,4-difluorophenyl)urea 1-(3,3-Dimethylbutyl)-1-[4-(n-butyl)benzyl]-3- 3039 (2,4-difluorophenyl)urea 1-(3,3-Dimethylbutyl)-1-[4-(n-butyl)benzyl]-3- 1337 (2,4,6-trichlorophenyl)urea 1-(5,5-Dime~hylhexyl)-1-[4-(n-butyl)benzyl]-3- 3442 (4-chloro-2-methylphenyl)urea (5~5-Dimethylhexyl)-l-[4-(n-butyl)benzyl]-3- 5~59 (2,4-difluorophenyl)urea _ .
TALE II (continued) Compound LO SO
1-(5,5-Dimethylhexyl)-1-[4-(n-butyl)benzyl~-3- 32 45 (2,4,6-trichlorophenyl)urea 1-(3,3-Dimethylbutyl)-1-(4-chlorobenzyl)-3- 60 50 (4-chloro-2-methylphenyl)urea 1-(3,3-Dimethylbutyl)-l-benzyl-3-(2,4-di- 70 71 fluorophenyl)urea I 1-(3,3-Dimethylbutyl)-1-(4-chlorobenzyl)-3- 69 43 (2,4-difluorophenyl)urea 1-(3,3-Dimethylbutyl)-1-(4-chlorobenzyl)-3- 70 85 (4-tri~luoromethylphenyl)urea 1-(3,3-Dimethylbutyl)-1-[4-(2,2-dimethyl- 19 35 propyl)benzyl]-3-(2,4-difluorophenyl)urea . 1-(3,3-Dimethylbutyl)-1-[4-(2,2-dimethyl- 20 51 propyl)benzyl]-3-(4-chloro-2-methylphenyl)urea 1-(3,3-Dimethylbutyl)-1-[4-(2,2-dimethyl- 15 32 propyl)benzyl]-3-(2,4,6-trichlorophenyl)urea 1-(3,3-Dimethylbutyl)-1-[4-(n-butyl)benzyl]-3- 12 28 (4-chloro-2,6-dimethylphenyl)urea 1-(3,3-Dimethylbutyl)-1-(4-chlorobenzyl)-3- 25 46 (4-chloro-2,6-dimethylphenyl)urea 1-(3,3-Dimethylbutyl)-1-[4-(2,2-dimethyl- 11 31 propyl)benzyl]-3-(4-chloro-2,6-dimethyl.-phenyl)urea 1-(3,3-Dimethylbutyl)-l-benzyl-3-(4-chloro-2- 51 64 methylphenyl)urea 1-(3,3-Dimethylbutyl)-l-(benzyl)-3-(4-chloro- ¦ 30 55 35 2,5-dimethylphenyl)urea 1-(3,3-Dimethylbutyl)~ 4-(n-butyl)benzyl]-3- 12 28 (4-chloro-2,5-dimethylphenyl)urea _ I
TABLE II (continued) Compound LO
1-(3,3-Dimethylbutyl)-1-[4-(2,2-dimethyl- 15 29 propyl)benzyl]-3-(4-chloro-2,5-dimethyl-phenyl)urea 1-[(4-Butylphenyl)methyl]-1-[3,3-dimethyl- 28 24 butyl]-3-[2,4,6-trifluorophenyl]urea l-Benzyl-1-[3,3-dimethylbutyl~-3-[2,4,6-tri- 77 57 fluorophenyl]urea 1-[3,3-Dimethylbutyl]-1-[4-(2,2-dimethyl- 17 19 propyl)phenyl]-3-[2,4,6-trifluorophenyl]urea 1-[(4-Isopropylphenyl)methyl]-1-(3-methyl- 37 butyl)-3-(2,4-difluorophenyl)urea 1-[(4-Isopropylphenyl)methyl]-1-(3-methyl- 23 butyl)-3-(4-chloro-2,6-dimethyiphenyl)urea 1-[(4-Isopropylphenyl)methyl]-1-(3-methyl- 35 butyl)-3-(2,4,6-trifluorophenyl)urea When the compounds are employed for the above utility, they may be combined with one or more forum-ceutically acceptable carriers, e.g., solvents, delineates, and the like, and may be administered orally in such forms as tablets, capsules, dispersible powders, granules, or suspensions containing, for example, from about 0.5 to 5%
of suspending agent, syrups containing, for example, prom about 10 to 50% of sugar, and elixirs containing, for example, from about 20 to 50% ethanol, and the like, or parenterally in the form of sterile injectable solutions or suspensions containing from about 0.5 to 5% suspending agent in an isotonic medium. These pharmaceutical prepay rations ma contain, for example, from about 0.5 up to about 90% or the active ingredient in combination with the carrier, more usually between 5 and 60~ by weight.
The anti atherosclerotic effective dosage of active ingredient employed may vary depending on the par-titular compound employed, the mode of administration, and the severity of the condition being treated. However, in general, satisfactory results are obtained when the come pounds of the invention are administered at a daily dosage of from about 2 my to about 500 mg/kg of animal body weight, preferably given in divided doses two to four times a day, or in sustained release form. For most large mammals, the total daily dosage is from about 100 my to about 5,000 my, preferably from about 100 my to 2,000 my.
Dosage forms suitable for internal use comprise from about 25 to 500 my of the active compound in intimate admixture with a solid or liquid pharmaceutically acceptable car-nor. This dosage regimen may be adjusted to provide the optimal therapeutic response. For example, several divided doses may be administered daily or the dose may be proper-tonally reduced as indicated by the exigencies of the therapeutic situation. A decided practical advantage is that these active compounds may be administered orally as well as by intravenous, intramuscular, or subcutaneous routes if necessary. Solid carriers include starch, fag-lose, dicalcium phosphate, microcrystalline cellulose sucrose and kaolin, while liquid carriers include sterile water, polyethylene glycols, non-ionic surfactants, and edible oils such as corn, peanut, and sesame oils, as are appropriate to the nature of the active ingredient and the particular form of administration desired. Adjutants customarily employed in the preparation of pharmaceutical compositions may be advantageously included, such as flay vowing agents, coloring agents, preserving agents, and antioxidant, e.g., vitamin En, ascorbic acid, BUT, and 30 BRA.
The preferred pharmaceutical compositions from the stand-point of ease of preparation and administration are solid compositions, particularly tablets and hard-filled or liquid-filled capsules. Oral administration of the compounds is preferred.
,, These active compounds may also be administered parenterally or intraperitoneally. Solutions or suspend sons of these active compounds as a free base or forum-ecologically acceptable salt can be prepared in water suit-5 ably mixed with a surfactant such as hydroxypropylcellu-lose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of micro-10 organisms.
The pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In all cases, the form must be sterile and must be fluid to the extent that easy syringability exists. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of micro-organisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g., glycerol, propylene glycol, and liquid polyethylene glycol), suitable mixtures thereof, and vegetable oils.
The preparation and properties of the compounds of this invention will be described in greater detail in conjunction with the specific examples shown below.
Example 1 3-(2,4-Difluorophenyl)-l-[[4-(2,2-dimethylpropYl) phenyl]methyl]-l-(n-heptyl)urea pa A solution of 6.73 g of 4-(neopentyl)benzoic acid and 13.0 ml of thinly chloride in 40 ml of dichloro-methane was heated at reflex for 4 hours. The reaction mixture was cooled and the solvent was evaporated in vacua. The residue was dissolved in dichloromethane and evaporated again. This step was repeated a second time and 4-(neopentyl)benzoyl chloride was obtained as a brown O i 1 .
I.
I
The preceding product was dissolved in 40 ml of dichloromethane and added with stirring to a cold solution of 4.04 g of Natalie amine and 9.8 ml of triethylamine in 60 ml of dichloromethane. The resulting mixture was stirred at room temperature for 16 hours. The mixture was diluted with water and two layers were separated. The organic layer was washed in succession with two 30 ml portions of 3 N hydrochloric acid. The solution was dried over an hydrous magnesium sulfate and filtered. The lit-irate was evaporated in vacua to yield 13.0 g of a Griswold. The solid was purified by preparative high pressure liquid chromatography on silica gel using ethyl acetate:-hexane (1:9) as the fluent. Several fractions were come brined and evaporated in vacua to yield 8.0 g of 4-(2,2-dimethylpropyl)-N-(n-heptyl)benzamide as a beige solid, my 58-60C.
A mixture of 7.5 g (0.026 moles) of the pro-ceding aside and 20 ml (0.052 moles) of Nitride T [sodium dihydrobis(2-methoxyethoxy)aluminate (70~ solution in Tulane)] in 80 ml of Tulane was reflexed for 4 hours, then cooled to room temperature. The complex was deco-posed by adding drops, 40 ml of 2.5 N sodium hydroxide with stirring during 30 minutes. The organic layer was separated and washed with brine, dried over an hydrous magnesium sulfate and filtered. The filtrate was vapor-axed to dryness in vacua to yield a yellow oil. Kugelrohr distillation (125C/0.15 mm of mercury) gave 5.45 g (90%) of4-(2,2-dimethylpropyl)-N-(n-heptyl)benzenemethanammine as a colorless liquid.
To a solution of 1.10 g (0.004 moles) of the preceding amine in 15 ml of hexane was added with stirring a solution of 0.62 g (0.004 moles) of 2,4-difluorophenyl-isocyanate in 15 ml of hexane. The resulting mixture was stirred at room temperature for 16 hours. The solvent was 35 evaporated in vacua to yield a colorless oil. Kugelrohr distillation (140-155C/0.15 mm of mercury) gave 1.44 g (84%) of the desired product as a colorless oil.
Example 2 3-(4-Chloro-2,6-dimethYlPhenyl)-1-~4-(2,2-dimethyll-propvl)phenyl]methyl]-l-(n-heptyl)urea To a mixture of 300 g t2.48 moles) of Dow-methyl aniline, 2.4 liters of dichloromethane and 24 ml of ethanol cooled at 5C in an ice bath was added an hydrous hydrogen chloride gas over a one hour period maintaining the reaction mixture temperature at 4-11C. Chlorine gas was passed through the mixture for approximately 2 hours 10 while the temperature was maintained at 5-10C during which time approximately 217 g of chlorine was introduced.
The reaction mixture was examined several times by thin layer chromatography using 10:1 ethyl acetate:hexane as a solvent system. Upon completion of the reaction, the 15 mixture was purged with argon gas, then allowed to stand at room temperature for 16 hours.
The mixture was cooled to 2C and filtered. The precipitate was washed with 250 ml of dichloromethane, followed by 1.5 liters of ether, and then air dried to 20 yield 371 g of 4-chloro-2,6-dimethylbenzeneamine mender-chloride.
To a suspension of the preceding monohydrochlor-ire 371 g (1.93 moles) in 1.5 liters of deathly ether maintained at 12-17C in an ice bath was added one liter 25 of 2 M sodium acetate solution over a 2~3 minute period with vigorous stirring. The mixture was stirred for 30 minutes then allowed to stand to separate 2 layers. The organic layer was washed in succession with one liter volumes of water, saturated sodium bicarbonate, then water again. The organic solution was dried over an hydrous sodium sulfate and filtered. Evaporation gave 288 g of solid. This solid was recrystallized from 800 ml of petrol Lomb ether and gave 229 g of 4~chloro-2l6-dimethylbenzene-amine as colorless crystals, my 47-50C.
To a cold solution of 2.47 g (0.0163 moles) of the above amine and 2.4 ml (0.0189 moles) of N,N-dimethyl-aniline in 80 ml of Tulane was added drops a solution . , of 2.56 g (0.0163 moles) of phenylchloroformate in 20 ml of Tulane. The resulting mixture was stirred at room temperature for 90 minutes then diluted with water. The organic layer was separated and washed with two 40 ml portions of 3 N hydrochloric acid, then with brine. The organic solution was dried over an hydrous magnesium sulfate and filtered. The filtrate was evaporated in vacua to yield a white solid. The solid was recrystallized from ethyl acetate:hexane to yield 3.8 g of phenyl(4-chloro-10 2,6-dimethylphenyl)carbamate as a white solid, my 158-160C.
A mixture of 1.11 g (0.004 moles) of the pro-ceding carbamate, 1.10 g (0.004 moles) of 4-(2,2-dimethyl-propyl)-N-(n-heptyl)benzenemethanamine (prepared in 15 Example 1) and 30 ml of Tulane was reflexed for 2 hours.
The solution was cooled, washed with two 30 ml portions of 1 _ sodium hydroxide, then with brine. The solution was dried over an hydrous magnesium sulfate and filtered. The filtrate was evaporated _ vacua to yield an oil. Cudgel-I roar distillation (145-155C/0.1 mm of mercury) gave 1.47 g of colorless oil which solidified on standing to yield the product of the Example as a white solid, my 111-113C.
Example 3 1-~[4-(2,2-Dimethylpropyl)phenyl]methyl]-l-(n-hepttwill)-3-(2,4,6-trifluorophenyl)urea To a cold solution of 5.3 g (0~0359 moles) of 2,4,6-trifluoroaniline and 5.6 ml (5.4 g, 0.044 moles) of N,N-dimethylaniline in 70 ml of Tulane was added drops a solution of 5.63 g (0.0359 moles) of phenol chloroform ate 30 in 20 ml of Tulane. The resulting mixture was stirred at room temperature for 16 hours and gave a precipitate. The mixture was diluted with ethyl acetate and water. The organic layer was separated and washed with two 50 ml portions of 3 N hydrochloric acid, then with two 50 ml 35 portions of brine. The solution was dried over an hydrous magnesium sulfate and filtered. The filtrate was vapor-.
I Ed axed in vacua to yield a solid. The solid was triturated with hexane, collected by filtration, washed with hexane and dried to yield 8.38 g ~96~) of phenyl(2,4,6-trifluoro-phenyl)carbamate as a white solid, my 127-128C.
A mixture of 0.97 g ~0.004 moles) of the pro-ceding carbamate, 1.10 g (0.004 moles) of 4-(2,2-dimethyl-propyl)-N-(n-heptyl)ben~enemethanamine (prepared in Example 1) and 40 ml of Tulane was reflexed or 2 hours.
The resulting solution was cooled, washed with two 30 ml 10 portions of 1 N sodium hydroxide, then with brine. The solution was dried over an hydrous magnesium sulfate, lit-toned and evaporated in vacua and gave a light yellow oil.
Kugelrohr distillation (140-150C/0.08 mm of mercury) gave 1.5 g of colorless oil. A 900 my portion of this oil was lo redistilled (140-150C/0.160 mm of mercury) to yield 500 my of the product of the Example as a colorless oil.
The ureas shown in Table III were prepared using the methods described in Examples 1-3.
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Claims (9)
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS;
1. A process for the preparation of a compound of the following formula (I):
(I) wherein, A is 4-(trifluormethyl)phenyl, 4-chloro 2-methylphenyl, 4-chloro-2,5-dimethylphenyl, 4-chloro-2,6-dimethylphenyl, 2,4-difluorophenyl, 2,4,6-trichlorophenyl, or 2,4,6--trifluorophenyl;
n is a positive integer from one to five;
R1 and R2 are independent of one another and are hydrogen or (C1-C4)alkyl; and Z is hydrogen, (C1-C5)alkoxy, halo or the group in which m is an integer from 0 to 5 and R3 and R4 are independent of one another and are hydrogen or (C1-C4)alkyl; with the proviso that R1, R2, R3, and R4 cannot all be hydrogen; characterized by reacting a compound of the following formula A-Y
wherein A is as defined above and Y is -N=C=O or -NH-CO-B, wherein B is halogen, (C1-C4)alkocy, (C1-C4)alkylthio, phenoxy, 4-chlorophenoxy or 4-nitrophenoxy; with a secondary amine of the formula;
wherein n, R1, R2, and Z are as defined above.
(I) wherein, A is 4-(trifluormethyl)phenyl, 4-chloro 2-methylphenyl, 4-chloro-2,5-dimethylphenyl, 4-chloro-2,6-dimethylphenyl, 2,4-difluorophenyl, 2,4,6-trichlorophenyl, or 2,4,6--trifluorophenyl;
n is a positive integer from one to five;
R1 and R2 are independent of one another and are hydrogen or (C1-C4)alkyl; and Z is hydrogen, (C1-C5)alkoxy, halo or the group in which m is an integer from 0 to 5 and R3 and R4 are independent of one another and are hydrogen or (C1-C4)alkyl; with the proviso that R1, R2, R3, and R4 cannot all be hydrogen; characterized by reacting a compound of the following formula A-Y
wherein A is as defined above and Y is -N=C=O or -NH-CO-B, wherein B is halogen, (C1-C4)alkocy, (C1-C4)alkylthio, phenoxy, 4-chlorophenoxy or 4-nitrophenoxy; with a secondary amine of the formula;
wherein n, R1, R2, and Z are as defined above.
2. A compound of the following formula (I):
(I) wherein A, R1, R2, and Z are as defined in Claim 1.
(I) wherein A, R1, R2, and Z are as defined in Claim 1.
3. A process for the preparation of 3-(2,4-difluorophenyl)-1-[[4 (2,2-dimethylpropyl)phenyl]methyl]-1-(n-heptyl)urea, which comprises reacting 2,4-difluorophenylisocyanate with 4-(2,2-dime-thylpropyl)-N-(n-heptyl)-benzenemethanamine.
4. The compound 3-(2,4-difluorophenyl)-1-[[4-(2,2-dimethyl-propyl)phenyl]methyl]-1-(n-heptyl)urea.
5. A process for the preparation of 3-(4-chloro-2,6-dimethyl-phenyl)-1-[[4-(2,2-dimethylpropyl)phenyl]methyl]-1-(n-heptyl)urea, which comprises reacting 4-chloro-2,6-dimethylbenzeneamine with phenyl chloroformate to yield phenyl(4-chloro-2,6-dimethylphenyl) carbamate which is reacted with 4-(2,2-dimethylpropyl)-N-(n-heptyl) benzenemethanamine.
6. The compound 3-(4-chloro-2,6-dimethylphenyl)-1-[[4-(2,2-dimethylpropyl)phenyl]methyl]-1-(n-heptyl)urea.
7. A pharmaceutical composition comprising as active ingred-ient, together with a pharmaceutically acceptable carrier therefor, a compound of the Formula (I) as defined in claim 2.
8. A composition according to claim 7 wherein the active ingredient is the compound of claim 4.
9. A composition according to claim 7 wherein the active ingredient is the compound of claim 6.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US51532183A | 1983-07-19 | 1983-07-19 | |
| US515,321 | 1983-07-19 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1239150A true CA1239150A (en) | 1988-07-12 |
Family
ID=24050874
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000459032A Expired CA1239150A (en) | 1983-07-19 | 1984-07-17 | Anti-atherosclerotic trisubstituted ureas |
Country Status (7)
| Country | Link |
|---|---|
| JP (1) | JPS6041655A (en) |
| AT (1) | AT394191B (en) |
| BE (1) | BE900178A (en) |
| CA (1) | CA1239150A (en) |
| FR (1) | FR2549473B1 (en) |
| GB (1) | GB2149394B (en) |
| NL (1) | NL8402272A (en) |
Families Citing this family (11)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CH642342A5 (en) * | 1979-09-13 | 1984-04-13 | Firmenich & Cie | PROCESS FOR THE PREPARATION OF MUSCON. |
| US5003106A (en) * | 1983-07-19 | 1991-03-26 | American Cyanamid Company | Antiatherosclerotic ureas and thioureas |
| US5032608A (en) * | 1986-09-10 | 1991-07-16 | Dudrick Stanley J | Method and substrate composition for treating atherosclerosis |
| US5248688A (en) * | 1986-09-10 | 1993-09-28 | Dudrick Medical Research Fund I, Ltd. | Method and substrate composition for treating atherosclerosis |
| US4994465A (en) * | 1989-02-17 | 1991-02-19 | Warner-Lambert Company | Antihyperlipidemic and antiatherosclerotic trisubstituted urea compounds |
| GB9020841D0 (en) * | 1990-09-25 | 1990-11-07 | Wellcome Found | Anti-atherosclerotic aryl compounds |
| ATE137744T1 (en) * | 1990-11-26 | 1996-05-15 | Taisho Pharmaceutical Co Ltd | ANILIDE DERIVATIVE |
| US5420164A (en) * | 1991-04-04 | 1995-05-30 | Yoshitomi Pharmaceutical Industries, Ltd. | Cycloalkylurea compounds |
| US5416212A (en) * | 1991-12-25 | 1995-05-16 | Taisho Pharmaceutical Co., Ltd. | Anilide derivatives |
| JPH05320143A (en) * | 1992-03-18 | 1993-12-03 | Mochida Pharmaceut Co Ltd | New pyrimidine derivative |
| US5378728A (en) * | 1992-11-03 | 1995-01-03 | Sandoz Ltd. | Benzoic acid derivatives as antidiabetic agents |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS5224104B2 (en) * | 1974-10-07 | 1977-06-29 | ||
| JPS5461149A (en) * | 1977-10-20 | 1979-05-17 | Kumiai Chem Ind Co Ltd | 3-chloro-4-fluorophenyl urea derivative, its preparation and herbicide containing the same |
| US4387105A (en) * | 1982-01-26 | 1983-06-07 | American Cyanamid Company | Methods of treating atherosclerosis with dialkylureas and dialkylthioureas |
| IL67417A (en) * | 1982-01-26 | 1989-10-31 | American Cyanamid Co | Antiatherosclerotic substituted ureas,process for their preparation and pharmaceutical compositions containing them |
| US4387106A (en) * | 1982-01-26 | 1983-06-07 | American Cyanamid Company | Method of treating atherosclerosis with di(aralkyl)ureas and di(aralkyl)thioureas |
-
1984
- 1984-07-05 GB GB08417126A patent/GB2149394B/en not_active Expired
- 1984-07-17 CA CA000459032A patent/CA1239150A/en not_active Expired
- 1984-07-17 AT AT0231284A patent/AT394191B/en not_active IP Right Cessation
- 1984-07-18 NL NL8402272A patent/NL8402272A/en not_active Application Discontinuation
- 1984-07-18 JP JP59147751A patent/JPS6041655A/en active Granted
- 1984-07-18 BE BE0/213345A patent/BE900178A/en not_active IP Right Cessation
- 1984-07-19 FR FR8411471A patent/FR2549473B1/en not_active Expired
Also Published As
| Publication number | Publication date |
|---|---|
| GB8417126D0 (en) | 1984-08-08 |
| GB2149394B (en) | 1986-09-24 |
| BE900178A (en) | 1985-01-18 |
| AT394191B (en) | 1992-02-10 |
| FR2549473B1 (en) | 1988-07-22 |
| NL8402272A (en) | 1985-02-18 |
| JPS6041655A (en) | 1985-03-05 |
| JPH0585543B2 (en) | 1993-12-07 |
| FR2549473A1 (en) | 1985-01-25 |
| GB2149394A (en) | 1985-06-12 |
| ATA231284A (en) | 1991-08-15 |
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