CA1334092C - Angiotensin ii receptor blocking imidazoles - Google Patents
Angiotensin ii receptor blocking imidazolesInfo
- Publication number
- CA1334092C CA1334092C CA000540399A CA540399A CA1334092C CA 1334092 C CA1334092 C CA 1334092C CA 000540399 A CA000540399 A CA 000540399A CA 540399 A CA540399 A CA 540399A CA 1334092 C CA1334092 C CA 1334092C
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- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
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- 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
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- 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
- A61P9/12—Antihypertensives
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- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/64—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
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- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D233/68—Halogen atoms
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D233/70—One oxygen atom
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D233/84—Sulfur atoms
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- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D233/90—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D233/91—Nitro radicals
- C07D233/92—Nitro radicals attached in position 4 or 5
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
- C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
- C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
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- C07—ORGANIC CHEMISTRY
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- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing aromatic rings
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
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- 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
- C07D405/10—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 carbon chain containing aromatic rings
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- 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
- C07D409/10—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 carbon chain containing aromatic rings
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- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/645—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having two nitrogen atoms as the only ring hetero atoms
- C07F9/6503—Five-membered rings
- C07F9/6506—Five-membered rings having the nitrogen atoms in positions 1 and 3
Abstract
Substituted imidazoles such as
Description
TITLE
ANGIOTENSIN II RECEPTOR BLOCKING IMIDAZOLES
R~CKGROUND OF T~F INVFNTION
Field of the Invention This invention relates to novel substituted imidazoles, and processes for their preparation, pharmaceutical compositions containing them and pharmaceutical methods using them.
The compounds of this invention inhibit the action of the hormone angiotensin II (AII) and are useful therefore in alleviating angiotensin induced hypertension. The enzyme renin acts on a blood plasma 2-globulin, angiotensinogen, to produce angiotensin I, which is then converted by angiotensin converting-enzyme to AII. The latter substance is a powerful vasopressor agent which has been implicated as a causative agent for producing high blood pressure in various mammalian species, such as the rat, dog, and man. The compounds of this invention inhibit the action of AII on its receptors on target cells and thus prevent the increase in boood pressure produced by this hormone-receptor interaction. By administering a compound of this invention to a species of mammal with hypertension due to AII, the blood pressure is reduced. The compounds of this invention are also useful for the treatment of congestive heart failure.
K. Matsumura, et al., in U.S. Patent 4,207,324 issued June 10, 1980 discloses 1,2-disubstituted-4-haloimidazole-5-acetic acid derivatives of the formula:
~ ,~
~r ~, y -1~ 1 3340q2 R2 N CH2CoOR3 5 ~ 3 R~
Wherein R i6 hydrogen, nitro or amino; R i6 phenyl, furyl or thienyl optionally 6ub6tituted by halogen, lower alkyl, lower alkoxy or di-lower alkylamino; R3 i6 hydrogen or lower alkyl and X i6 halogen; and their phy6iologically acceptable 6alt6. The6e compound6 have diuretic and hypoten6ive action6.
Furukawa, et al., in U.S. Patent 4,355,040 i~6ued October 19, 1982 di6clo6e6 hypoten6ive imidazole-5-acetic acid derivative6 having the formula:
Rl ~ ~ CH2CO2R2 xl 2 X3 Wherein Rl i6 lower alkyl, cycloalkyl, or phenyl optionally 6ub6tituted; Xl, X2, and X3 are each hydrogen, halogen, nitro, amino, lower alkyl, lower alkoxy, benzyloxy, or hydroxy; Y i6 halogen and R2 i6 hydrogen or lower alkyl: and 6alt6 thereof.
Furukawa, et al., in ~.S. Patent 4,340,598, i~6ued July 20, 1982, di6clo6e6 hypoten6ive imidazole derivative6 of the formula:
R l 33409 ~
lN ~
Rl wherein R1 is lower alkyl or, phenyl Cl_2 alkyl optionally substituted with halogen or nitro; R2 is lower alkyl, cycloalkyl or phenyl optionally substituted;
one of R3 and R4 is -(CH2)nCoR5 where R5 is amino, lower alkoxyl or hydroxyl and n is 0, 1, 2 and the other of R3 and R4 is hydrogen or halogen; provided that R1 is lower alkyl or phenethyl when R3 is hydrogen, n=1 and R5 is lower alkoxyl or hydroxyl; and salts thereof.
Furukawa et al., in European Patent Application 103,647 published 1984 March 28 discloses 4-chloro-2-phenylimidazole-5-acetic acid derivatives useful for treating edema and hypertension of the formula:
Cl ~ N~ CH2CO2H
lCH2 ~ ~R
OH
Where R represents lower alkyl and salts thereof.
The metabolism and disposition of hypotensive agent 3Q 4-chloro-1-(4-methoxy-3-methylbenzyl)-2-phenylimidazole-5-acetic acid is disclosed by H. Torii in Takeda Kenkyushoho, 41, No 3/4, 180-l91 (1982).
Frazee et al., in European Patent Application 125,033-A published 1984 November 14 discloses 1-phenyl(alkyl)-thioimidazole derivatives which are inhibitors of dopamine-~-hydroxylase and are useful ~`
as antihypertensives, diuretics and cardiotonics.
European Patent Application 146,228 published 1985 June 26 by S.S.L. Parhi discloses a process for the preparation of l-substituted-5-hydroxymethyl-2-mercaptoimidazoles.
A number of references disclose 1-benzylimidazoles such as U.S. Patent 4,448,781 to Cross and Dickinson (issued May 15, 1984); U.S. Patent 4,226,878 to Ilzuka et al. (issued October 7, 1980); U.S. Patent 3,772,315 to Regel et al. (issued November 13 1973); U.S. Patent 4,379,927 to Vorbruggen et al. (issued April 12, 1983);
amongst others.
Pals et al., Circulation Research, 29, 673 (1971) desc~ibe the introduction of a sarcosine residue in position 1 and alanine in position 8 of the endogenous vasoconstrictor hormone AII to yield an (octa)peptide that blocks that effects of AII on the blood pressure of pithed rats. This analog, [Sarl, Ala8]AII, initially called "P-113" and subsequently "Saralasin", was found to be one of the most potent competitive antagonists of the actions of AII, although, like most of the so-called peptide-AII-antagonists, it also possesses agonistic actions of its own. Saralasin has been demonstrated to lower arterial pressure in mammals and man when the (elevated) pressure is dependent on circulating AII (Pals et al., Circulation Research, 29, 673 (1971); Streeten and Anderson, Handbook of Hypertension, Vol. 5, Clinical Pharmacology of Antihypertensive Drugs, A. E. Doyle (Editor), Elsevier Science Publishers B.V., p. 246 (1984)). However, due to its agonistic character, saralasin generally elicits pressor effects when the pressure is not sustained by AII.
Being a peptide, the pharmacological effects to ....~ ~.
-1 33409~
saralasin are relatively short-lasting and are only manifest after parenteral adminir-tration, oral doses being ineffective. Although the therapeutic uses of peptide AII-blockers, like saralasin, are ~everely limited due to their oral ineffectiveness and short duration of action, their major utility is as a pharmaceutical standard.
To date there are no known non-peptide antagonists of AII which are useful orally or which bind in vitro in the IC50 ranges we observe.
Summary Of The Invention According to the present invention there are provided novel compounds of formula (I) which have angiotensin II-antagonizing properties and are u~eful as antihypertensives.
N~,R~
lt R7 R6/ \N~
CH2), R1 ~
(I) wherein R is -4-C02H; -4-C02R ; -O-S-OH; -S03H, OH
,o, 1l 1 33409~
--C(CF3)20H; --O- P--OH ; --PO3H; --NH--P--OH
OH OH
~I NHSO2CH3; 4--NHSO2CF3; _CoNHoRl2;
OH(~ N--N
--SO2NH2 ; --C--P--OH ; ~ N
4 ~ ,N ; 4-X~F3 ; ~X~F;
N HC3 4-X~
Il / R13 N--N
4-CO~ N ; 1CONHNHSO2CF3 ; 4--CONHCHCH2C6H5 (I isomer) 4-CO--N~ (I isomer); ~--R11 ~4 N~--CF3;
4 ~yNH ; 4--xb ; ~\,J
_ j R is H; Cl; Br; I; F; NO2; alkyl of 1 to 4 carbon atoms; acyloxy of 1 to 4 carbon atoms; alkoxy of 1 to 4 carbon atoms; CO2H; CO2R ; NHSO2CH3; NHSO2CF3:
CONHOR : 5O2NH2 : ~ ~ : aryl: or furyl;
R3 is ~; Cl, Br, I or F: al~yl of 1 to 4 carbon atoms or alkoxy of 1 to 4 carbon atoms:
R is CN, NO2 or CO2Rll:
R5 i6 H, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms alkenyl or alkynyl of 2 to 4 carbon atoms;
R6 is alkyl of 2 to 10 carbon atoms, alkenyl or lS alkynyl of 3 to 10 carbon atoms or the same groups substituted with P or Co2R14: cycloalkyl of 3 to 8 carbon atoms, cycloalkylalkyl, of 4 to 10 carbon atoms; cycloalkylalkenyl or cycloalkylalkynyl of 5 to 10 carbon atoms:
(CH2)~Z(CH2)mR optionally substituted with F or CO2R : benzyl or benzyl substituted on the phenyl ring with 1 or 2 halogens, alkoxy of 1 to 4 carbon atoms, alkyl of 1 to 4 carbon atoms or nitro;
R7 is H, F, Cl, Br, I, NO2, CF3 or CN;
R8 i5 H, CN, alkyl of 1 to 10 carbon atoms, alkenyl of 3 to 10 carbon atoms, or the same groups substituted witb F: pbenylalkenyl wherein the aliphatic portion is 2 to 6 carbon atoms:
-(CH2)m-imidazol-1-yl: -(CH2)m-1,2,3-triazolyl optionally ybstituted wit~ one or two groups selected from CO2CH3 or alkyl of 1 to 4 carbon atoms; -(CH2)m-tetrazolyl;
-(CH2)nOR ; -(CHz)nOCR ; -(CH2)nSRlS:
-_ ` 8 1 334092 R14 o O
-CH=CH(CH2)6CHoR15: -CH=CH(CH2)sCR16: -CR16;
-CH=CH(CH2)~OCR
O Y
(CH2)s-CH-COR ; -(CH2)nCR ; -(CH2)nOCNHR
Y O
-(CH2)nNRllCOR ; -(CH2)nNR lCNHR ; -(CH2)nNR115O2Rl ;
-(CH2)nNRllCRlO; -(CH2)~F; ~CH2)mONO2;-CH2N3;
-(CH2)~N02; t CH2)~-N ~ ;
R24 o 9 ~ ~ 21 R is -CH-OCR
R10 is alkyl of 1 to 6 carbon atoms or perfluoro-alkyl of 1 to 6 carbon atoms, l-adamantyl, l-naphthyl, l-(l-naphthyl)ethyl, or (CH2)pC6H5:
R is H, alkyl of 1 to 6 carbon atoms, cyclo-alkyl of 3 to 6 carbon atoms, phenyl or benzyl;
R12 is H, methyl or benzyl:
R is -CO2H; -CO2R ; -CH2CO2H, -CH2CO2R ;
O O O
.. .. ..
-O-S-OH; -O-P-OH; -SO3H; -NHP-OH
OH OH OH
- PO3H2; - C ( CF3)2OH; -NHSO2CH3; -NHSO2CF3; -NHCOCF3;
,~ ~
1 3340~2 _ o9 O ~-N
-CONHOR12: -502NH2; ' " ~ ,N ;
R27 OH N~3 N-N~ ~-N~
-CH ~ N ~ -CONH ~N~N ; -CONHNH502cF3 ~ C~
R14 is H, alkyl or perfluoroalkyl of 1 to 8 carbon atoms, cycloalkyl of 3 to 6 carbon atom~, phenyl or benzyl;
R15 is H, alkyl of 1 to 6 carbon atoms, cyclo-alkyl of 3 to 6 carbon atoms, phenyl, benzyl, acyl of 1 to 4 carbon atoms, phenacyl R16 is H, alkyl of 1 to 6 carbon atoms, cyclo-oRl7 or NRlBRl9 p R17 is H, alkyl of 1 to 6 carbon atoms, cyclo-alkyl of 3 to 6 carbon atoms, phenyl or benzyl;
R15 and Rl9 independently are H, alkyl of 1 to 4 carbon atoms, phenyl, benzyl, a-methylbenzyl, or taken together with a nitrogen atom form a ring of the form~la ~ \ 2)t N ~ Q
Q iS NR20, O or CH2;
R is H, alkyl of 1-4 carbon atoms, or phenyl;
R 1 is alkyl of 1 to 6 carbon atoms, -NR22R2 , or ,C 2 2 3 Q g v 1 3~4uq2 R and R 3 independently are H, alkyl of 1 to 6 carbon atoms, benzyl, or are taken together a6 (CH2)U where u i6 3-6;
R i6 H, CH3 or -C6H5;
R i6 NR R , OR , NHCONH2, NHCSNH2, -~HSo2~3c~ or -t~Hso2~3;
R26 i6 hydrogen, alkyl with from 1 to 6 carbon atom6, benzyl, or allyl:
R27 and R are independently hydrogen, alkyl with from 1 to S carbon atom6, or phenyl;
R29 and R30 are independently alkyl of 1-4 carbon atom6 or taken together are ~(CH2)q~;
R31 i6 H, alkyl of 1 to 4 carbon atom6, -CH2CH=CH2 or -CH2C6H4R 2;
R i6 H, NO2, NH2, OH or OCH3;
X i6 a carbon-carbon 6ingle bond, -CO-, -O-, -S-, -NH-, -N- , -CON- , -NCO-, -OCH2-, -CH2O-, -SCH2-, -CH2S-, -NHC(R27)(R28), -NR23So -, SO NR23 C(R27)(R28)NH-~ -CH=CH-, -CF=CF-, -CH=CF-, -CF=CH-, -CH2CH2-, -CF2CF2-, ~ , oRl4 oCOR17 NR25 R O OR
\/
-CH- , -CH- , -C- or -~- ;
30 Y i6 O or S;
Z i6 O NRll or S;
m i6 1 to 5;
n i6 1 to 10:
p i6 0 to 3;
q i6 2 to 3;
~0 s is 0 to 5, 1 334092 t is 0 or 1;
and pharmaceutically acceptable salts of these compounds;
provided that:
(1) the Rl group i~ not in the ortho position:
al3 (2) when Rl is ~ ~ , X i~ a single bond, ~ ~3 R
and R13 is C02H, or ~ N ~ then R13 must be in the ortho or meta position; or when and X are as above and R13 is NHS02CF3 or 2 3' must be ortho;
ANGIOTENSIN II RECEPTOR BLOCKING IMIDAZOLES
R~CKGROUND OF T~F INVFNTION
Field of the Invention This invention relates to novel substituted imidazoles, and processes for their preparation, pharmaceutical compositions containing them and pharmaceutical methods using them.
The compounds of this invention inhibit the action of the hormone angiotensin II (AII) and are useful therefore in alleviating angiotensin induced hypertension. The enzyme renin acts on a blood plasma 2-globulin, angiotensinogen, to produce angiotensin I, which is then converted by angiotensin converting-enzyme to AII. The latter substance is a powerful vasopressor agent which has been implicated as a causative agent for producing high blood pressure in various mammalian species, such as the rat, dog, and man. The compounds of this invention inhibit the action of AII on its receptors on target cells and thus prevent the increase in boood pressure produced by this hormone-receptor interaction. By administering a compound of this invention to a species of mammal with hypertension due to AII, the blood pressure is reduced. The compounds of this invention are also useful for the treatment of congestive heart failure.
K. Matsumura, et al., in U.S. Patent 4,207,324 issued June 10, 1980 discloses 1,2-disubstituted-4-haloimidazole-5-acetic acid derivatives of the formula:
~ ,~
~r ~, y -1~ 1 3340q2 R2 N CH2CoOR3 5 ~ 3 R~
Wherein R i6 hydrogen, nitro or amino; R i6 phenyl, furyl or thienyl optionally 6ub6tituted by halogen, lower alkyl, lower alkoxy or di-lower alkylamino; R3 i6 hydrogen or lower alkyl and X i6 halogen; and their phy6iologically acceptable 6alt6. The6e compound6 have diuretic and hypoten6ive action6.
Furukawa, et al., in U.S. Patent 4,355,040 i~6ued October 19, 1982 di6clo6e6 hypoten6ive imidazole-5-acetic acid derivative6 having the formula:
Rl ~ ~ CH2CO2R2 xl 2 X3 Wherein Rl i6 lower alkyl, cycloalkyl, or phenyl optionally 6ub6tituted; Xl, X2, and X3 are each hydrogen, halogen, nitro, amino, lower alkyl, lower alkoxy, benzyloxy, or hydroxy; Y i6 halogen and R2 i6 hydrogen or lower alkyl: and 6alt6 thereof.
Furukawa, et al., in ~.S. Patent 4,340,598, i~6ued July 20, 1982, di6clo6e6 hypoten6ive imidazole derivative6 of the formula:
R l 33409 ~
lN ~
Rl wherein R1 is lower alkyl or, phenyl Cl_2 alkyl optionally substituted with halogen or nitro; R2 is lower alkyl, cycloalkyl or phenyl optionally substituted;
one of R3 and R4 is -(CH2)nCoR5 where R5 is amino, lower alkoxyl or hydroxyl and n is 0, 1, 2 and the other of R3 and R4 is hydrogen or halogen; provided that R1 is lower alkyl or phenethyl when R3 is hydrogen, n=1 and R5 is lower alkoxyl or hydroxyl; and salts thereof.
Furukawa et al., in European Patent Application 103,647 published 1984 March 28 discloses 4-chloro-2-phenylimidazole-5-acetic acid derivatives useful for treating edema and hypertension of the formula:
Cl ~ N~ CH2CO2H
lCH2 ~ ~R
OH
Where R represents lower alkyl and salts thereof.
The metabolism and disposition of hypotensive agent 3Q 4-chloro-1-(4-methoxy-3-methylbenzyl)-2-phenylimidazole-5-acetic acid is disclosed by H. Torii in Takeda Kenkyushoho, 41, No 3/4, 180-l91 (1982).
Frazee et al., in European Patent Application 125,033-A published 1984 November 14 discloses 1-phenyl(alkyl)-thioimidazole derivatives which are inhibitors of dopamine-~-hydroxylase and are useful ~`
as antihypertensives, diuretics and cardiotonics.
European Patent Application 146,228 published 1985 June 26 by S.S.L. Parhi discloses a process for the preparation of l-substituted-5-hydroxymethyl-2-mercaptoimidazoles.
A number of references disclose 1-benzylimidazoles such as U.S. Patent 4,448,781 to Cross and Dickinson (issued May 15, 1984); U.S. Patent 4,226,878 to Ilzuka et al. (issued October 7, 1980); U.S. Patent 3,772,315 to Regel et al. (issued November 13 1973); U.S. Patent 4,379,927 to Vorbruggen et al. (issued April 12, 1983);
amongst others.
Pals et al., Circulation Research, 29, 673 (1971) desc~ibe the introduction of a sarcosine residue in position 1 and alanine in position 8 of the endogenous vasoconstrictor hormone AII to yield an (octa)peptide that blocks that effects of AII on the blood pressure of pithed rats. This analog, [Sarl, Ala8]AII, initially called "P-113" and subsequently "Saralasin", was found to be one of the most potent competitive antagonists of the actions of AII, although, like most of the so-called peptide-AII-antagonists, it also possesses agonistic actions of its own. Saralasin has been demonstrated to lower arterial pressure in mammals and man when the (elevated) pressure is dependent on circulating AII (Pals et al., Circulation Research, 29, 673 (1971); Streeten and Anderson, Handbook of Hypertension, Vol. 5, Clinical Pharmacology of Antihypertensive Drugs, A. E. Doyle (Editor), Elsevier Science Publishers B.V., p. 246 (1984)). However, due to its agonistic character, saralasin generally elicits pressor effects when the pressure is not sustained by AII.
Being a peptide, the pharmacological effects to ....~ ~.
-1 33409~
saralasin are relatively short-lasting and are only manifest after parenteral adminir-tration, oral doses being ineffective. Although the therapeutic uses of peptide AII-blockers, like saralasin, are ~everely limited due to their oral ineffectiveness and short duration of action, their major utility is as a pharmaceutical standard.
To date there are no known non-peptide antagonists of AII which are useful orally or which bind in vitro in the IC50 ranges we observe.
Summary Of The Invention According to the present invention there are provided novel compounds of formula (I) which have angiotensin II-antagonizing properties and are u~eful as antihypertensives.
N~,R~
lt R7 R6/ \N~
CH2), R1 ~
(I) wherein R is -4-C02H; -4-C02R ; -O-S-OH; -S03H, OH
,o, 1l 1 33409~
--C(CF3)20H; --O- P--OH ; --PO3H; --NH--P--OH
OH OH
~I NHSO2CH3; 4--NHSO2CF3; _CoNHoRl2;
OH(~ N--N
--SO2NH2 ; --C--P--OH ; ~ N
4 ~ ,N ; 4-X~F3 ; ~X~F;
N HC3 4-X~
Il / R13 N--N
4-CO~ N ; 1CONHNHSO2CF3 ; 4--CONHCHCH2C6H5 (I isomer) 4-CO--N~ (I isomer); ~--R11 ~4 N~--CF3;
4 ~yNH ; 4--xb ; ~\,J
_ j R is H; Cl; Br; I; F; NO2; alkyl of 1 to 4 carbon atoms; acyloxy of 1 to 4 carbon atoms; alkoxy of 1 to 4 carbon atoms; CO2H; CO2R ; NHSO2CH3; NHSO2CF3:
CONHOR : 5O2NH2 : ~ ~ : aryl: or furyl;
R3 is ~; Cl, Br, I or F: al~yl of 1 to 4 carbon atoms or alkoxy of 1 to 4 carbon atoms:
R is CN, NO2 or CO2Rll:
R5 i6 H, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms alkenyl or alkynyl of 2 to 4 carbon atoms;
R6 is alkyl of 2 to 10 carbon atoms, alkenyl or lS alkynyl of 3 to 10 carbon atoms or the same groups substituted with P or Co2R14: cycloalkyl of 3 to 8 carbon atoms, cycloalkylalkyl, of 4 to 10 carbon atoms; cycloalkylalkenyl or cycloalkylalkynyl of 5 to 10 carbon atoms:
(CH2)~Z(CH2)mR optionally substituted with F or CO2R : benzyl or benzyl substituted on the phenyl ring with 1 or 2 halogens, alkoxy of 1 to 4 carbon atoms, alkyl of 1 to 4 carbon atoms or nitro;
R7 is H, F, Cl, Br, I, NO2, CF3 or CN;
R8 i5 H, CN, alkyl of 1 to 10 carbon atoms, alkenyl of 3 to 10 carbon atoms, or the same groups substituted witb F: pbenylalkenyl wherein the aliphatic portion is 2 to 6 carbon atoms:
-(CH2)m-imidazol-1-yl: -(CH2)m-1,2,3-triazolyl optionally ybstituted wit~ one or two groups selected from CO2CH3 or alkyl of 1 to 4 carbon atoms; -(CH2)m-tetrazolyl;
-(CH2)nOR ; -(CHz)nOCR ; -(CH2)nSRlS:
-_ ` 8 1 334092 R14 o O
-CH=CH(CH2)6CHoR15: -CH=CH(CH2)sCR16: -CR16;
-CH=CH(CH2)~OCR
O Y
(CH2)s-CH-COR ; -(CH2)nCR ; -(CH2)nOCNHR
Y O
-(CH2)nNRllCOR ; -(CH2)nNR lCNHR ; -(CH2)nNR115O2Rl ;
-(CH2)nNRllCRlO; -(CH2)~F; ~CH2)mONO2;-CH2N3;
-(CH2)~N02; t CH2)~-N ~ ;
R24 o 9 ~ ~ 21 R is -CH-OCR
R10 is alkyl of 1 to 6 carbon atoms or perfluoro-alkyl of 1 to 6 carbon atoms, l-adamantyl, l-naphthyl, l-(l-naphthyl)ethyl, or (CH2)pC6H5:
R is H, alkyl of 1 to 6 carbon atoms, cyclo-alkyl of 3 to 6 carbon atoms, phenyl or benzyl;
R12 is H, methyl or benzyl:
R is -CO2H; -CO2R ; -CH2CO2H, -CH2CO2R ;
O O O
.. .. ..
-O-S-OH; -O-P-OH; -SO3H; -NHP-OH
OH OH OH
- PO3H2; - C ( CF3)2OH; -NHSO2CH3; -NHSO2CF3; -NHCOCF3;
,~ ~
1 3340~2 _ o9 O ~-N
-CONHOR12: -502NH2; ' " ~ ,N ;
R27 OH N~3 N-N~ ~-N~
-CH ~ N ~ -CONH ~N~N ; -CONHNH502cF3 ~ C~
R14 is H, alkyl or perfluoroalkyl of 1 to 8 carbon atoms, cycloalkyl of 3 to 6 carbon atom~, phenyl or benzyl;
R15 is H, alkyl of 1 to 6 carbon atoms, cyclo-alkyl of 3 to 6 carbon atoms, phenyl, benzyl, acyl of 1 to 4 carbon atoms, phenacyl R16 is H, alkyl of 1 to 6 carbon atoms, cyclo-oRl7 or NRlBRl9 p R17 is H, alkyl of 1 to 6 carbon atoms, cyclo-alkyl of 3 to 6 carbon atoms, phenyl or benzyl;
R15 and Rl9 independently are H, alkyl of 1 to 4 carbon atoms, phenyl, benzyl, a-methylbenzyl, or taken together with a nitrogen atom form a ring of the form~la ~ \ 2)t N ~ Q
Q iS NR20, O or CH2;
R is H, alkyl of 1-4 carbon atoms, or phenyl;
R 1 is alkyl of 1 to 6 carbon atoms, -NR22R2 , or ,C 2 2 3 Q g v 1 3~4uq2 R and R 3 independently are H, alkyl of 1 to 6 carbon atoms, benzyl, or are taken together a6 (CH2)U where u i6 3-6;
R i6 H, CH3 or -C6H5;
R i6 NR R , OR , NHCONH2, NHCSNH2, -~HSo2~3c~ or -t~Hso2~3;
R26 i6 hydrogen, alkyl with from 1 to 6 carbon atom6, benzyl, or allyl:
R27 and R are independently hydrogen, alkyl with from 1 to S carbon atom6, or phenyl;
R29 and R30 are independently alkyl of 1-4 carbon atom6 or taken together are ~(CH2)q~;
R31 i6 H, alkyl of 1 to 4 carbon atom6, -CH2CH=CH2 or -CH2C6H4R 2;
R i6 H, NO2, NH2, OH or OCH3;
X i6 a carbon-carbon 6ingle bond, -CO-, -O-, -S-, -NH-, -N- , -CON- , -NCO-, -OCH2-, -CH2O-, -SCH2-, -CH2S-, -NHC(R27)(R28), -NR23So -, SO NR23 C(R27)(R28)NH-~ -CH=CH-, -CF=CF-, -CH=CF-, -CF=CH-, -CH2CH2-, -CF2CF2-, ~ , oRl4 oCOR17 NR25 R O OR
\/
-CH- , -CH- , -C- or -~- ;
30 Y i6 O or S;
Z i6 O NRll or S;
m i6 1 to 5;
n i6 1 to 10:
p i6 0 to 3;
q i6 2 to 3;
~0 s is 0 to 5, 1 334092 t is 0 or 1;
and pharmaceutically acceptable salts of these compounds;
provided that:
(1) the Rl group i~ not in the ortho position:
al3 (2) when Rl is ~ ~ , X i~ a single bond, ~ ~3 R
and R13 is C02H, or ~ N ~ then R13 must be in the ortho or meta position; or when and X are as above and R13 is NHS02CF3 or 2 3' must be ortho;
(3) when Rl is ~ ~ , and X is other than ~ ~3 a ~ingle bond, then R13 must be ortho except when ~ = NR C0 and R is NHS02C~3 or NHS02CH3. then R must be ortho or meta;
(4) when R is 4-C02H or a salt thereof, R6 cannot be S-alkyl;
(5) when R is 4-C02H or a salt thereof, the substituent on the 4-position of the imidazole cannot be CH20H, CH20COCH3, or CH2C02H;
Rl3 1 334092 (6) when R is ~ ~ , X i6 -OCH2-, and ~2 3 R i6 2-CO2H, and R i6 H then R i6 not C2H5S:
Rl3 1 334092 (6) when R is ~ ~ , X i6 -OCH2-, and ~2 3 R i6 2-CO2H, and R i6 H then R i6 not C2H5S:
(7) when Rl i6 -CONH ~ , and R6 i~ n-hexyl then R7 and R8 are not both hydrogen;
(8) when Rl i6 -NHCO ~ , R6 i6 not methoxy-benzyl;
lS , 2 2 3 2 Preferred for their antihyperten6ive activity arenovel compound6 having the formula:
~ 2 (II) 13 1 3340~
Wherein ~13 Rl is -CO2H; -NHSO2CF3; ~ \N ;
and ~ al3 R6 is alkyl of 3 to 10 carbon atoms, alkenyl of 3 to 10 carbon atoms, alkynyl of 3 to 10 carbon atoms, cycloalkyl of 3 to 8 carbon atoms, benzyl substituted on the phenyl ring with up to two groups selected from alkoxy of 1 to 4 carbon atoms, halogen, alkyl of 1 to 4 carbon atoms, and nitro:
R8 is phenylalkenyl w~erein the aliphatic portion is 2 to 4 carbon atoms, -(CH2)m-imidaZl--(CH2)m-1,2,3-triazolyl optionally sub6ti-tuted with one or two groups selected from C02CH3 or alkyl of 1 to 4 carbon atoms, o (CH2)m-tetrazolyl, -(CH2)nORl ; -(CH2)nocRl4:
-CH=CH(CH2)~CR16, -CH=CH(CH2)6CHOR
O O
-(cH2)ncR ; _(cH2)nNHcoR ; ~(CH2)nNHS2Rl ;
O
-(CH2)mF; -CR16;
R13 is -CO2H, -CO2R , NHSO2CF3; and ~ ~ ;
N' 14 1 3340~
R is H, alkyl of 1 to 5 carbon atoms, OR , or NR R
X is carbon-carbon single bond, -CO-, -CON- , 2 H2 ~ -,N2CO3-, -OCH2-, -CH2O-, -SCH2-, -CH2S-, -NHCH2-, -CH2NH- or -CH=CH-: and pharmaceutically acceptable salts of these compounds.
More preferred are compounds of the preferred scope where:
R is H, alkyl of 1 to 4 carbon atoms, halogen, or alkoxy of 1 to 4 carbon atoms:
R6 is alkyl, alkenyl or alkynyl of 3 to 7 carbon atoms;
R7 is H, Cl, Br, or CF3;
R is -(CH2)mOR ; -(CH2)mOCR : -CH=CH-CHOR 5:
O O
-(CH2)mCR16: -CH2NHCOR10;
-(CH2)mNHSO2R ; CH ~ ~N ; or -COR
H
R10 is CF3, alkyl of 1 to 6 carbon atoms or phenyl;
R is H, or alkyl of 1 to 4 carbon atoms;
R13 is CO2H; C02CH2OCOC(CH3)3; NHS02CF3 and ~\ -t ' H
1 3~4092 R i~ H, or alkyl of 1 to 4 carbon atoms;
R is H, alkyl of 1 to 4 carbon atoms, or acyl of 1 to 4 carbon atoms;
R is H, alkyl of 1 to 5 carbon atoms; opl : or r__~
O
m i~ 1 to 5;
X = ~ingle bond, -0-; -C0-; -NHC0-; or -OCH2-; and pharmaceutically acceptable salt~.
Specifically preferred for their antihypertensive activity are:
2-Butyl-4-chloro-1-t~2'-(lH-tetrazol-.5-yl)biphen-yl-4-yl)methyl~-5-(hydroxymethyl)imidazole.
Z-Butyl-4-chloro-1-t(2'-carboxybiphenyl-4-yl)-methyl]-5-(hydroxymethyl)imidazole.
2-Butyl-4-chloro-1-~(2'-carboxybiphenyl-4-yl)-methyl]-5-[(methoxycarbonyl)aminomethyl]imidazole.
2-Butyl-4-chloro-l-t(2l-carboxybiphenyl-4-yl)-methyl]-5-[(propoxycarbonyl)aminomethyl]imidazole.
2-Butyl-4-chloro-1-[(2'-carboxybiphenyl-4-yl) methyl]imidazole-5-carboxaldehyde 2-Butyl-1-[(2'-carboxybiphenyl-4-yl)methyl]-imidazole-5-carboxaldehyde 2-(lE-Butenyl)-4-chloro-1-[(2'-carboxybiphenyl-g-yl)methyl]-5-(hydroxymethyl)imidazole 2-(lE-Butenyl)-4-chloro-1-[(2'-carboxybiphenyl-4-yl)methyl]imidazole-5-carboxaldehyde 2-Propyl-4-chloro-1-[2'-(lH-tetrazol-5-yl)biphenyl-4-yl)methyl~-5-(hydroxymethyl)imidazole 2-Propyl-4-chloro-1-t2'-(lH-tetrazol-5-yl)biphenyl-4-yl)methyl~imidazole-5-carboxaldehyde 2-Butyl-4-chloro-1-t2'-(lH-tetrazol-5-yl)biphenyl-4-yl)methyl~imidazole-5-carboxaldehyde 16 1 3~40q 2 2-(lE-Butenyl)-4-chloro-1-~2'-(lH-tetrazol-5-yl)biphenyl-4-yl)methyl]-5-hydroxymethyl)imidazole 2-(lE-Butenyl)-4-chloro-1-[2'-(lH-tetrazol-5-yl)biphenyl-4-yl)methyl]imidazole-5-carboxaldehyde and pharmaceutically acceptable 6alts thereof.
Note that throughout the text when an alkyl substituent is mentioned, the normal alkyl structure i6 meant (i.e., butyl is n-butyl) unless otherwi6e 6pecified.
Al60 within the 6cope of thi6 invention are pharmaceutical compositions compri6ing a 6uitable pharmaceutical carrier and a compound of Formula (1), and methods of usinq the compounds of Formula (I) to treat hypertension and conge6tive heart failure. The compounds of this invention can also be used a6 diagnostic agents to test the renin angiotensin 6ystem.
It 6hould be noted in the foregoing 6tructural formula, when a radical can be a 6ubstituent in more than one previously defined radical, that fir6t radical can be selected independently in each pre-viously defined radical. For example, Rl, R2 and R3 can each be CONHOR12. R12 need not be the 6ame 6ubstituent in each of Rl, R2 and R3 but can be selected independently for each of them.
Synthesis The novel compounds of Formula (I) may be prepared using the reaction6 and technique6 described in this section. The reactions are performed in a 601Yent appropriate to t~e reagentc and material~
employed and suitable for the transformation being effected. It is understood by those skilled in the art of organic synthesis that the functionality present on the imidazole and other portions of the 17 1 3340~
molecule must be consistent with the chemical transformations proposed. This will frequently necessitate judgment as to the order of synthetic steps, protecting groups required, deprotection conditions, and activation of a benzylic position to enable attachment to Ditrogen on the imidazole nucleus. Throughout the following 6ection, not all compounds of formula (~) falling into a given class may necessarily be prepared by all method~ described for that class. Substituents on the starting materials may be incompatible with 60me of the reaction conditions reguired in some of the methods described. Such restrictions to the 6ubstituents which are compatible with the reaction conditions will be readily apparent to one skilled in the art and alternative methods described must then be used.
Scheme1 1 334092 R3--~Ni 2) ,~CH2X R
/X = Br, Cl, OTs, OMs NHr NH3 ~ R1- 4-NO2 NH2 7 or o R7 or R8 R~ +R6~ N ~ R7 or R8 ~ R H
R~l 4 5 6 ~2~\R3 NH o R6~NH (HO)C~ R8 N~ RR7 b) , n~ , ~
N--, R8 \¢3 CN R N 1 ~--R7 H base ~
N ,~ RR7 ~/ CN CO2H
~H
11 N~N
N - N~
Generally, compounds of Formula (3) can be prepared by direct alkylation onto imidazole (1) prepared as described in U.S. 4,355,040 and references cited therein, with an appropriately protected benzyl halide, tosylate or mesylate (2) in the pre~ence of base, as shown in path a). Preferably, the metallic imidazolide salt is prepared by reacting imidazole (1) with a proton acceptor such a~- MH where M i6 lithium, sodium or potassium in a solvent such as dimethylformamide (DMF) or by reacting it with a metal alkoxide of formula MOR where R is methyl, ethyl, t-butyl or the like in an alcohol solvent such a8 ethanol or t-butanol, or a dipolar aprotic solvent such as dimethylformamide. The imidazole ~alt i6 dissolved in an inert aprotic solvent such a~ DMF, and treated with an appropriate alkylating agent (2).
Alternatively, imidazole (1) can be alkylated with a benzyl halide (2, where X=Br, Cl) in the presence of a base such as sodium carbonate, potassium carbonate, triethylamine or pyridine. The reaction is run in an inert solvent such as DMF or DMSO at 20C to the reflux temperature of the solvent for 1-10 hour~.
For example, the 4-nitrobenzyl intermediate (3a, wherein Rl = 4-N02, R2 ~ R3 = H) may be obtained by direct alkylation onto imidazole (1) with a 4-nitrobenzyl halide, tosylate or mesylate in the presence of base.
If R and R are different, mixtures of two regioisomer alkylation products (3b, and 3c) are obtained in which R7 and R8 are interchanged.
When R is CHO the alkylaSion is 8uch that the benzyl group becomes attached to the adjacent nitrogen preferentially. These isomers possess distinct physical and biological properties and can usually be separated and isolated by conventional separation techniques such as chromatography and~or crystallization.
-1 33409~
1~ p8 R6~ R9 RI~R
1~ ~
~ 3c 3d; R6 = n-Bu, R7 - Cl3e; R6 , n-Bu, 10R = CH2C02Me, R7 = Cl R8 ~ CH20H
R = 4-NHC ~3 Rl ~ 4~H
15CF3S02N I~J
R2 , R3 . H
R = R = H
In all 6erie6 examined, the more rapidly eluted i60mer of a given pair has greater biological potency than the le66 rapidly eluted i60mer. The absolute 6tructure of the compound6 3d and 3e has been confirmed by X-ray cry6tallographic analy6i6 to e6tabli6h the relation6hip between structure, phy6ical propertie6 and biological activity. Sulfonamide 3d i6 the more rapidly eluted i60mer in it6 serie6, acid 3e i6 the le6s rapidly eluted i60mer in it6 6erie6.
Alternatively, any properly functionalized benzylamine derivative (4) may be converted to imine (6) by treatment with an acylamino ketone (5) in the pre6ence of an inert 601vent such a6 benzene, toluene, or the like, and a catalytic amount of p-toluene-6ulfonic acid or molecular sieve6, N. Engel, and W. Steglich, Liebiq6 Ann. Chem., 1916, (197B), or in the pre6ence of alumina, F. Texier-Boulet, SYnthe6i 679 (19~5). The re6ulting imine (6) can be cyclized 21 1 3340q2 to the N-benzyl imidazole (3) with phosphorus penta-chloride (PC15), phosphorus oxychloride (POC13) or triphenylphosphine (PPh3) in dichloroethane in the pre6ence of a base 6uch a6 triethylamine, N. Engel and W. Steglich, Liebiq6 Ann. Chem., 1916, (1978).
Acylamino ketone (5) i6 readily obtainable from amino acid6 via the Dakin-We6t reaction, H.D. Dakin, R. We6t, J. Biol. Chem., 78, 95 and 745 (1928), and various modification6 thereof, W. Steglich, G. Hofle, Anqew. Chem. Int. Ed. Enql., 8, 981 (1969); G. Hofle, W. Steglich, H. Vorbr~ggen, Anqew. Chem. Int. Ed.
Enql., 17, 569 (1978); W. Steglich, G. Hofle, Ber., 102, 883 (1969), or by selective reduction of acyl cyanides, A. Pfaltz, S. Anwar, Tet. Lett. 2977 (1984), or from a-halo, a-to6yl or a-mesyl ketone6 via the appropriate 6ubstitution reactions that one skilled in the art will readily recognize.
The functionalized benzylamine6 (4) may be made from the corre6ponding benzyl halide, tosylate or mesylate (2) via di6placement with a nitrogen nucleo-phile, a procedure familiar to one skilled in the art. Thi6 di6placement may be achieved using azide ion, ammonia, or phthalimide anion, etc., in a neutral 601vent such as dimethylformamide, dimethyl6ulfoxide etc., or under phase transfer condition6. The benzyl halide (2) may be made by a variety of benzylic halo-genation methods familiar to one 6killed in the art, for example benzylic bromination of toluene derivative6 with N-bromo6uccinimide in an inert solvent 6uch a6 carbon tetrachloride in the pre6ence of a radical initiator 6uch a6 benzoyl peroxide at temperature6 up to reflux conditions.
A wide variety of toluene derivatives may be made rom simple electrophilic 6ubstitution reactions on an aromatic ring. Thi6 includes nitration, 6ulfonation, -22 1 33409~
phosphorylation, Friedel-Craft6 alkylation, Friedel-Crafts acylation, halogenation, and other similar reactions known to one skilled in the art, G. A. Olah, "Friedel-Crafts and Related Reaction6," Vol. 1-5, s Inter~cience, New York, (1965).
Another way to 6ynthe6ize functionalized benzyl halide6 is via chloromethylation of the corresponding aromatic precur60r. Thu6, the appropriately 6ub6ti-tuted benzene ring may be chloromethylated with formaldehyde and hydrochloric acid (HCl) for example with or without an inert solvent such a6 chloroform, carbon tetrachloride, light petroleum ether or acetic acid. A Lewi6 acid such as zinc chloride (ZnC12) or a mineral acid 6uch a6'pho6phoric acid may al60 be added a6 a cataly6t or conden6ing agent, R. C. Fu60n, C. H. McKeever, Orq. Reactions, 1, 63 (1942).
Alternatively, N-benzylimidazole6 (3) can al60 be prepared a6 shown in path b) by orming an R 6ub-6tituted amidine (7) from an appropriately ~ub6tituted benzylamine (4) which i6 in turn reacted with an a-haloketone, a-hydroxyketone (8), a-haloaldehyde, or a-hydroxyaldehyde, F. Kunckell, Ber., 34, 637 ( 1901 ) .
As 6hown in path a), imidazole (1) may be alkylated by a variety of benzyl derivative6. The6e include compounds with latent acid functionalitie6 6uch as o, m, and p-cyanobenzylhalide6, me6ylate6 or to6ylate6 as 6hown in path c). Nitrile6 of formula (9) may be hydrolyzed to carboxylic acid6 of formula (10) by treatment with strong acid or alkali. Prefer-ably, treatment with a 1:1 (v/v) mixture of concen-trated aqueous hydrochloric acid/glacial acetic acid at reflux temperatures for 2-96 hours or by treatment with lN sodium hydroxide in an alcohol solvent 6uch as ethanol or ethylene glycol for 2-96 hours at tempera-23 1 3340~2 tures from 20C to reflux can be used. If anothernitrile group is present it will al~o be hydrolyzed.
The nitrile functionality can also be hydrolyzed in two steps by first stirring in sulfuric acid to form the amide followed by hydrolysi6 with sodium hydroxide or a mineral acid to give the carboxylic acid (10).
The nitriles (9) can be converted into the corresponding tetrazole derivative (11) by a variety of methods using hydrazoic acid. For example, the nitrile can be heated with ~odium azide and ammonium chloride in DM~ at temperatures between 30C and reflux for 1-10 day~, J. P. Hurwitz and A. J. Tomson, J. Orq. Chem., 26, 3392 (1961). Preferably, the tetrazole is prepared by the l,3-dipolar cycloaddition Of trialkyltin or triaryltin azides to the appropriately substituted nitrile as described in detail by Scheme 15.
The starting imidazole compounds (1) are readily available by any of a number of standard methods. For example, acylaminoketone (5) can be cyclized with ammonia or equivalents thereof, D. Davidson, et al., J. Orq. Chem., 2, 319 (1937) to the corresponding imidazole as ~hown in Scheme 1. The corresponding oxazole can also be converted to imidazole (1) by action of ammonia or amines in general, H. Bredereck, et al., Ber., 88, 1351 (1955); J. W. Cornforth and R. H. Cornforth, J. Chem Soc., 96, (1947).
Several alternative routes to imidazoles (1) are illustrated in Scheme 2. As shown in Scheme 2 equa-tion a), reaction of the appropriate R6 substitutedimidate esters (12) with an appropriately substituted a-hydroxy- or a-haloketone or aldehyde (8) in ammonia leads to imidazoles of formula (1), P. Dziuron, and W. Schunack, Archiv. Pharmaz., 307 and 470 (1974).
-24 1 3340~2 The 6tarting imidazole compounds (1) wherein R and R are both hydrogen can be prepared as shown in equation b) by reaction of the appropriate R6-substituted imidate ester (12) with a-aminoacetaldehyde dimethyl acetal (13), ~. R.
Grimmett, Adv. ~eterocyclic Chem., 12, 103 (1970).
As 6hown in equation c), imidazole (15: wherein R = hydrogen and R = CH20H) can be prepared by treatment of the imidate ester (12) witb 1,3-dihydroxyacetone (14) in ammonia by the procedure described in Archive der Pharmazie, 307, 470 (1974).
Halogenation of imidazole (15) or any imidazole wherein R or R8 is hydrogen is preferably accom-pli6hed by reaction with one to two equivalent6 of N-halosuccinimide in a polar solvent such as dioxane or 2-methoxyethanol at a temperature of 40-100C for 1-10 hours. Reaction of the halogenated imidazole (16) with a benzylhalide (2) in the manner described in Scheme 1 affords the corresponding N-benzylimidazole (17); wherein R7 is halogen and R8 is CH20H). This procedure i6 described in U.S. Patent 4,355,040.
Alternatively, imidazole (17) can be prepared by the procedure described in U.S. Patent 4,207,324.
Compounds of formula (17) can also be prepared by treatment of the starting imidazole compound (1) wherein R7 and R8 are both hydrogen, with the appro-priate benzyl halide followed by functionalization of R7 and R8 by treatment with formaldehyde as de6cribed in E. F. Godefroi, et al., Recueil, 91, 1383 (1972) followed by halogenation as was described above.
As shown in equation d) the imidazoles (1) can also be prepared by reaction of R6 sub6tituted amidines (18) with an a-hydroxy- or a-haloketone or aldehyde (8) as described by F. ~unckel, Ber., 34, 637, (1901).
1 3340q 2 As shown in equation e), preparation of the nitroimidazoles (1, R or R = N02) is preferably accomplished by heatin~ the appropriate starting imidazole in a 3:1 mixture of conc. sulfuric acid/conc. nitric acid at 60-100C for 1-6 hours.
Nitration of t~e imidazole (15) can be achieved by first converting the hydroxymethylimidazole to tbe corresponding chloromethylimidazole (22) employing thionyl chloride or oxalyl chloride. Nitration, as described above, followed by hydrolysis provides the nitroimidazoles (24).
Imidazoles (21) where R7 and R8 = CN can be prepared as ~hown in equation f) by reaction of R6 substituted ortho e~ters, ortho acids or aldehydes (followed by oxidation of the aldehyde) with diamino-maleonitrile (20) by the procedure described by R. W.
Begland et al., J. Orq. Chem., 39, 2341 (1974). Like-wise, R6 substituted imidate esters (12) also react with diaminomaleonitrile to give 4,5 dicyanoimidazoles (21). The nitrile groups can be further elaborated into other functional groups by methods familiar to one skilled in the art.
a) NH-HCI l 334092 R6 OCH2CH3 (Cl)HO~ R8 NH3 b) 12 + H2NCH2CH(OMe)2 ~R6 ~ ;~
(wherein R7=R3=H) c) 12 + CCH2oOH ~ R61 N~OH
/ halogenation X ~ X
N~,OH , R61 H X=Br,CI H
16 ~\J--R3 NH
R6J~ NH2 + (Cl)HO~ R3 X,' _ 27 1 3~40q2 S .~ .
R6J~;~3 cl HNO3/H2SO4 ~CI
NO
N
NH
CN
H2N CN N ~
f) R3--C(OMe)3 + ~( R6--~N~--CN
19 or 12 R7 Rs = CN
~, ~' Scheme3 7 1 3 3 4 0 9 2 a) 61 ~CH20H ,Q 'RCH2CI ~N ~RCH2CN
R1~\R2R3 R~\R2R3 R1~ J2R3 17(where R7=CI) 2 N--R7 R6~N~--CO2CH3 or NaOH l ~ I
1~R2 R1~ R2R3 N ~:H2oCR14 b) 17(R C )2~
or Tl --R3 R14COCI 1/~ R2 R
6~ H20R11 c) 17 ~ N ~ ?5 \~ ~\J2 N ~CF3 N ~.l 8 _~ ' R8 R N CF3Cu d) ~ - R3 R,~R2R3 ,,~;,~
29 1 33409~
A6 6hown in Scheme 3, path a) for benzylimid-azole6 (17) where R = Cl and R = CH20H, the hydroxy-methyl g~oup6 may be ea6ily converted to the corre-6ponding halide, me6ylate or to6ylate by a variety o$ method6 familiar to one 6killed in the art.
Preferably, the alcohol (17) is converted to the chloride (25) with thionyl chloride in an inert 601vent at temperature~ of 20C to the reflux temperature of the 601vent.
Chloride (25) may be di6placed by a variety of nucleophile6 by nucleophilic di6placement reaction procedure6 familiar to one 6killed in the art. For example, exce6s 60dium cyanide in DMS0 may be u6ed to form cyanomethyl derivative6 (26) at temperature6 of 20C to 100C.
Nitrile (26) may be hydrolyzed to acetic acid derivative (27), by a variety of method6. The6e method6 include method6 de6cribed previou61y for the hydroly6i6 of nitrile6 of formula (9). Example6 of de6ired acid6 and ba6e6 for thi6 hydroly6i6 include mineral acid6 6uch a6 6ulfuric acid, hydrochloric acid, and mixture6 of either of the above with 30-50%
acetic acid (when 601ubility i6 a problem), and alkali metal hydroxide6 6uch a6 60dium hydroxide or pota66ium hydroxide. The hydroly6i6 reaction proceed6 under heating at temperature6 ranging from 50-160C for 2-48 hour6. Carboxylic acid (27) may be e6terified by a variety of method6 without affecting other part6 of the molecule.- Preferably, (27) i6 refluxed in a hydrochloric acid/methanol 601ution for 2-48 hour6 to qive e6ter (2~).
E6ter (28) may be hydrolyzed to carboxylic acid (27), for in6tance, after R , R and R3 have been elaborated. Variou6 method6, acidic or ba6ic, may be u6ed. For example, compound (28) i6 6tirred with 0.5N
-potassium hydroxide in methanol, or if base ~oluble, it is stirred in l.ON sodium hydroxide for 1-48 h at 20C to reflux temperatures.
Hydroxymethyl derivative (17) may be acylated to give (29) by a variety of procedures. As shown in path b) acylation can be achieved with 1-3 equivalents of an acyl halide or an anhydride in a 601vent ~uch as diethyl ether, tetrahydrofuran, methylene chloride or the like in the presence of a base such as pyridine or triethylamine. Alternatively (17) may be acylated by reaction witb a carboxylic acid and dicyclohexylcarbo-diimide (DCC) in the presence of a catalytic amount of 4-(N,N-dimethylamino)pyridine (DMAP) via the procedure described by A. Hassner, Tet. Lett., 46, 4475 (1978).
Treatment of (17) with a solution of carboxylic acid anhydride in pyridine optionally with a catalytic amount of DMAP at temperatures of 20-100C for 2-48 hours is the preferred method.
The ether (30) can be prepared from the alcohol (17) as shown in path c) by methods such as treatment of (17) in a solvent such as dimethylformamide or dimethylsulfoxide with potassium t-butoxide, sodium hydride, or the like followed by treatment with RllL
at 25C for 1-20 hours, where L is a halogen, tosylate or mesylate.
Alternatively, treatment of (17) with l-S
equivalents of thionyl chloride in chloroform for 2-6 hours at 25C followed by treatment of the intermediate (25) with 1-3 equivalents of MOR 1, where M is 60dium or potassium, for 2-10 hours at 25C either in RllOH
as solvent or in a polar solvent 6uch as dimethylform-amide or the like will also yield ether (30).
The ether (30) can also be prepared for example by hea~ting (17) for 3-lS hours at 60-160C in R OH
containing an inorganic acid such as a hydrochloric acid or sulfuric acid.
-31 1 3340~
Compound (17) can be dehalogenated to compound (31) preferably by catalytic hydrogenoly6i6 (over an appropriate cataly6t 6uch a6 lOS palladium on carbon) in methanol at 25C for 1-6 hour6 or by treatment with zinc metal in acetic acid.
A6 6hown in Scheme 3, the trifluoromethyl imidazole6 (33) can be prepared from the corresponding iodoimidazole6 (32) by treatment with trifluoromethyl copper, J. Am. Chem. Soc., 108, 832 (1986).
N-arylimidazole6 of formula I (compound6 wherein r=o) can be prepared by the following method6, it being under6tood by one 6killed in the art that certain manipulations, protecting and deprotecting step6, and other 6ynthetic procedure6 di6clo6ed above may be nece66ary to produce compounds with the de6ired combination6 of R , R , R and R13-A6 shown in Scheme 4, equation a) the reactionof aniline derivative (34) with imidate e6ter (12) to form the sub6tituted amidine (35) provide6 material which can be cyclized with dihydroxyacetone to form 6tructure (36). Subsequent elaboration into (I) provides the N-arylimidazole compound6 of the invention.
Alternatively as 6hown by equation b) the Marckwald procedure, de6cribed by Marckwald et al., Ber., 22, 568, 1353 (1889): Ber., 25, 2354 (1892) can be u6ed to form a 2-mercaptoimidazole (38) from aniline derivative (34) via isothiocyanate (37).
De6ulfurization of (38) with dilute nitric acid followed by anion formation at the 2-position of the imidazole (39) and reaction with R6X where X is Cl, Br, I, allow6 the formation of (40) which can be 6ub6equently elaborated to I.
A variation of ~arckwald'6 proces~ a6 6hown in equation c) using an a-aminoketone (41) and isothiocyanate (37) can al60 be employed, 6ee Norri6 and McKee, J. Amer. Chem. Soc., 77, 1056 tl955) can also be employed. Intermediate (42) can be converted to (1~ by known 6equence6. The general procedure of Carboni et al., J. Amer. Chem. Soc., 89, 2626 (1967) (illustcated by equation d)) can al60 be u6ed to prepare N-aryl substituted imidazole6 from appropriate haloaromatic compounds (43; X=F, Cl, Br) and imidazole6 (1):
Scheme 4 ~H
2 o~t ~ R13 ~ R13 Co(cH2oH) \~
R6'~ R6 ~ <
~ 3 ~H ~ Rl3 Scheme 4 (continued) HS ~~;;3 b) ¢1 ~ 1) H2NCH2CH(OEt)2 ~1 ~3_ R13 ~3_ R13 3_ R13 HNO3, R6~ 3 N;~
(1) nBuLi ~3_ R13 ~_ R13 HS ~~
c) R8COCH2NH2 + 37 ~ I
3_ R13 42 N ~ R3 X R6--~N~ 7 N~ R8 ~ Na2CO3 hR
H R + ~_ DMF ~_ R13 ~ I
~ 1 3340~2 In various synthetic routes Rl~ R2 and R3 do not necessarily remain the same from the starting compound to the final products, but are often manipulated through known reactions in the intermediate steps as shown in Schemes 5-~2. All of the transformations shown in Sch~mes 5-10 and 12 can also be carried out on the terminal aromatic ring (i.e., biphenyl ring).
Scheme 5 R6 ~ N~ R IN ~0] R N, (CH2)r (CH2)r (CH2)r R ~ R2R ~-SH R 3~J
44 ~ 46 As shown in Scheme 5, compounds where R1 is a sulfonic acid group may be prepared by oxidation of the corresponding thiol (45). Thus, an N-benzylimidazole derivative bearing a thiol group may be converted into a sulfonic acid (46) by the action of hydrogen peroxide, peroxyacids such as metachloroperoxybenzoic acid, potassium permanganate or by a variety of other oxidizing agents, E.
E. Reid, Org~n;c Chem1stry of Biv~lent Sulfur, 1, Chemical Publishing Co., New York, 120-121 (1958).
~ 35 I 3~4092 Aromatic hydroxy or thiol group6 are obtained from deprotection of the corre6ponding alkyl ether or thioether6. Thu6, for example, a methyl ether or a methyl thioether derivative (44) of an N-benzylimid-azole containing one or more aromatic rings may beconverted into the free phenol or thiophenol (45) by the action of boron tribromide ~ethyl ~ulfide, P. G.
Willard and C. F. Fryhle, Tet. Lett., 21, 3731 (1980):
trimethylsilyl iodide, ~. E. Jung and M. A. Ly6ter, J. Orq. Chem., ~2, 3761 (1977); RSEt and derivative6 thereof, G. I. Feutrill, R. N. ~irrington, Tet. Lett., 1327, (1970), and a variety of other reagent6.
Alternatively, N-benzylimida201es may be sulfonated by 6tirring vith H2S04 at a variety of different concentrations or with other sulfonating agent6 6uch a6 chlorosulfonic acid or sulfur trioxide with or without complexing agents ~uch a6 dioxane or pyridine at temperature6 from O to 200C with or with-out 601vent, K. LeRoi Nel60n in Friedel-Craft6 and Related Reaction6, III part 2, G. A. Olah, ed., Inter6cience Publ., 1355 (1964).
The 6ynthe6i6 of compound6 where Rl i6 a 6ulfate, pho6phate or pho6phonic acid are depicted in Scheme 6:
Scheme 6 N~ R3 R N
(cH2)r (CH2)r ~J R2~--o~ - OH
47 ~CI5 48 \\~ ~ R7 (CH2)r R2~J OP- OH
b) 61 ~ - R7 R6 ~N~ 1 ~ R7 (CH2)r AIC13 (cH2)r (CIH2)r R2~ PC12 ~--PC4 ~;where R1 = H 50 51 N~R
~; R7 PSCI3 H2 (CH2)r AICI3 ~5~ 0 R2~`/~ IP--OH
Scheme 6 (continued) 1 334~q2 R N . ~ N ~ R87 (CH2)r Cu(l) (CH2)r ~--N2+X- 2~J PCI3X-54 X = BF4, SiF6, ZnCI3 N~,R37 R N + 3HCI
(cH2)r 2~--P--OH
N--R37 ~ ; R7 (CH2)r + (EtO)3P ~ (CH2)r ~ 52 R2~3/B(cl) 3~ OEt 5~ R2, R3, R4 ~ halogen (EtO)3P
NiX2 (X = Halogen) -38 1 3340~2 N-Benzylimidazoles containing a phenolic hydroxyl group 147) may be readily converted into the corresponding sulfate (48) or phosphate (49). As shown in equation a), reaction of the phenol with a sulfur trioxide-amine complex will give the corre-sponding sulfate (48), E. E. Gilbert, Sulfonation and Related Reactions, Interscience, New York, chapter 6 (1965). Reaction of the phenol (97) with phosphorus pentachloride followed by hydrolysis will give the corresponding phosphate (49), G. M. ~osolapoff, Organophosphorus Compounds, John Wiley, New Yor~, 235 (1950).
As shown in equation b) N-benzylimidazoles may be converted into the corresponding phosphonic acids by reaction with phosphorus trichloride (PC13) and aluminum chloride (AlC13) in an inert sol~ent for 0.5-96 hours from temperatures of 25C to the reflux temperatures of the solvent. Appropriate workup followed by reaction with chlorine (C12) and subsequent hydrolysis of the tetrachloride (51) gives the phosphonic acid derivative (52), G. M. Kosolapoff in Orq. Reactions, 6, R. Adams, editor, John Wiley and Sons, New York, 297 (1951). Another more direct route involves reaction of the N-benzylimidazole with PSC13 and AlC13 followed by hydrolysis, R. S.
Edmunson in Comprehensive Orqanic Chemistry, Vol. 2, D. Barton and W. D. Ollis editors, Pergamon Press, New York, 1285 (1979).
Alternatively, equation c) illustrates that aryl phosphonic acids (52) may be formed from reaction of the corresponding diazonium salt (53) with PC13 in the presence of Cu(I) followed by hydrolysis with water (ibid, p. 1286).
As shown in equation d), the aryl halides (55) may be photolyzed in the presence of phosphite esters to give phosphonate esters (56), R. Kluger, J. L. W.
39 1 3340q2 Chan, J. Am. Chem. Soc., 95, 2362, (1973). These same aryl halides also react with phosphite ester6 in the presence of nickel or palladium salts to give pho6-phonate esters, P. Tav6, Chem. Ber., 103, 242B (1970), which can be subsequently converted to phosphonic acid6 (52) by procedures known to one skilled in the art.
N-Benzylimidazoles containing an aldehyde or ketone (57) may be reacted with a phosphorus trihalide followed by water hydroly6i6 to give a-hydroxypho6-phonic acid derivative6, G.M. ~0601apoff, op. cit., 304, as 6hown in Scheme 7.
Scheme 7 N ~,8 ; R6 2~ ~120 20(cH2)r (CH2)r R2R~ CR R ~ - r-H
S7 ~R ~ R, ~ lltyll58 ~J
-1 3340~2 Compounds where R is -CONHOR may be pre-pared as shown in Scheme 8, by the treatment of a carboxylic acid (10) with 1-4 equivalents of thionyl chloride for 1-10 hours. This reaction can be run without sol~ent or in a nonreactive solvent such as benzene or chloroform at temperatures of 25-65C. The intermediate acid chlor~de is then treated with 2-10 equivalents of the appropriate amine derivative, H2N-OR , for 2-18 hours at temperatures of 25-80C
in a polar aprotic solvent such as tetrahydrofuran or dimethylsulfoxide to give the hydroxamic acid (59).
Scheme 8 R6 N > R6 N
~C~2H ~3-WDR12 ~
,~
Alternatively, the carboxylic acid (10) can be converted to the hydroxamic acid (59) according to the procedure in J. Med. Chem., 28, 1158 (1985) by employing dicyclohexylcarbodiimide, l-hydroxybenzo-triazole, and H2NOR or according to the procedure described in SYnthesis~ 929 (1985) employing the Vilsmeier reagent and H2NOR
Scheme 9 ~ 3340q2 ~ R7 ~ R7 ~ ;;; R7 (CH2)r (CH2)r ~ (CH2)r R ~ ~ CN3 21~--N=C=O
N~ R 7 ~ ~ R7 R-OH ~ N
R= alkyl, i.e. (CIH2)r (CH2)r (CH3)3SiCH2CH2 ,~--NHCOR '~ NH2 Aniline intermediate6 (63) are di6clo6ed in U.S.
Patent No. 4,355,040 and may be obtained from the corresponding nitro compound precur60r by reduction.
A variety of reduction procedure6 may be u6ed 6ucb a6 iron~acetic acid, D. C. Ow~ley, J. J. Bloomfield, Synthesi6, 118, (1977), 6tannou6 chloride, ~. D.
Bellamy, Tet. Lett., 839, (1984) or careful hydro-genation over a metal cataly6t 6uch a6 palladium.
A6 6hown in Scheme 9, aniline intermediate6 of N-benzylimidazole6 may al60 be prepared from the corre-6ponding carboxylic acid (10) or acid chloride via a Curtius rearrangement of an intermediate acyl azide (60). More modern method6 include u6ing diphenyl-pho6phoryl azide as a ~ource of azide, T. Shioiri, K. Ninomiya, S. Yamada, J. Am. Chem. Soc., 94, 6203 (1972), and trapping the intermediate i60cyanate (61) produced by the Curtius rearrangement witb 2-trimethyl-6ilylethanol and cleaving the re6ultant carbamate (62) with fluoride to liberate the amine (63), T. L. Cap60n and C. D. Poulter, Tet. Lett., 25, 3515 (1984).
Cla66ical procedures familiar to one 6killed in the art may al60 be employed.
Compound6 where Rl i6 -502NH2 may be made a6 6hown in Scheme 10:
-Scheme 10 1 3~40~2 ~ R6 ~ ~ R
(CH2)r (CH2)r ~ 502C1 2 ~ so 6~ ~
Sulfonamide compoun~s (65) may be made by reacting an arylsulfonyl chloride (64) with ammonia, or it6 equivalent. Unsub6tituted aryl6ulfonamide6 are made by reaction with ammonia in aqueous 601ution or in an inert organic 601vent, F. H. Bergheim and W. Braker, J. Am. Chem. Soc., 66, 1459 (1944), or with dry powdered ammonium carbonate, E. H. Huntre66 and J. S. Autenrieth, J. Am. Chem. Soc., 63, 3446 (1941):
E. H. Huntre66 and F. H. Carten, J. Am. Chem. Soc., 62, 511 (1940).
The sulfonyl chloride precur60r may be prepared by chlorosulfonation with chloro6ulfonic acid on the aromatic ring directly, E. H. Huntre66 and F. H.
Carten, ibid.; E. E. Gilbert, oP. cit., 84, or by reacting the corre6ponding aromatic diazonium chloride 6alt (53) with 6ulfur dioxide in the pre~ence of a copper cataly6t, H. Meerwein, et al., J. Prakt. Chem., tii], 152, 251 (1939), or by reacting the aromatic 6ulfonic acid (46) with PC15 or POC13, C. M. Suter, The Organic Chemi6trY of Sulfur, John Wiley, 459 (1948).
Linked ester compounds of formula (I) where R
o is -CO2CH(R )OCR can be made by procedures well known in penicillin and cephalosporin chemistry.
The purpose is to provide materials which are more lipophilic and which will be useful orally by rapid transit from the qut into the bloodstream, and which will then cleave at a sufficiently rapid rate to provide therapeutically useful concentrations of the active carboxylic acid form. The following review articles and references cited therein discuss this concept and the chemistry involved in preparing such compounds V. J. Stella, et al., Druqs, 29, 455-473 (1985); H. Ferres, Drugs of Today. 19 (9), 499-538 (1983); A. A. Sirkula, Ann. Repts. Med. Chem., 10, 306-315 (1975).
Experimental procedures which are applicable to the preparation of chemically stable linked esters are illustrated by equations a-e of Scheme 11.
Scheme 11 (a) RCO2Na + (CH3)3CC02CH2Br ~RC02CH2OCOC(CH3)3 G. Francheschi et al., J. Antibiotics, ~6, (7), 938-941 (1983).
(b) RCO2 + (CH3)2NCON(CH3)2 + ClCHOCOC(CH3)3 RCO2CHOCOC(CH3)3 J. Budavin, U.S. Patent 4,440,942 R~24 (c) RC02H ` RC02CH-OCOCHCH2C02CH3 -B. Daehne et al., G.B. Patent 1,290,787 25 (d)RCO2H > RCo2CHCONR22R23 Ferres, Chem. Ind., 435-440 (1980) 3 (e) R-CO2H > RHC ~
~ ' ,. ..
~, 46 1 3340~2 Clayton et al., Antimicrob. Aqents ChemotheraPY, 5, (6), 670-671 (1974) ln equations a-e: R= R 4 ~
R2~3 Compounds of Formula I where Rl is -C(CF3)20H
may be prepared as 6hown in Scheme 12.
Scheme 12 1 33409~
~; R7 N~ R87 --SiMe3 R3 CF3 71 ~2 ,~"~
.
llexafluoroisopropanol compounds (72) may be prepared by treatment of arylsilane (71) with 1-5 equivalents of hexafluoroacetone in a solvent such as methylene chloride at temperatures ranging from about -50 to 25C for a period of 2-10 hours. The requisite arylsilane (71) can be prepared using methods known to one skilled in the art such as the procedures described iQ Chapter 10 of Butterworth's "Silicon in Organic Chemistry".
Scheme 13 1 334092 N-- R87 1 ' R7 N-- R87 ~NO2 ~ NH2 >X3 3a 63 73 R13 H]
R8 / reductive ~R8 1 ~ R7 amination ; R7 ~
N--Z ~ (R23 ~ H
'23 o 76 z= ,ll3 HOC
77 Z=
o 78 Z=
1 3340q2 As shown in Scheme 13, compound (73) in which X=
-NHCO and R13= -COOH may be easily prepared, for example, by reacting aniline precursor (63) with a phthalic anhydride derivative in an appropriate solvent such as benzene, chloroform, ethyl acetate, etc. Often the carboxylic acid product will precipi-tate from solution with the reactants remaining behind, M.L. Sherrill, F.L. Schaeffer, E.P. Shoyer, J. Am.
Chem. Soc., 50, 474 (1928).
When R =NHS02CH3, NHS02CF3 or tetrazolyl (or a variety of other carboxylic acid equivalents), compound (73) may be obtained by reacting aniline (63) with the requisite acid chloride by either a Schotten-Baumann procedure, or simply stirring in a solvent such as methylene chloride in the presence of a base such as sodium bicarbonate, pyridine, or triethylamine.
Likewise, aniline (63) may be coupled with an appropriate carboxylic acid via a variety of amide or peptide bond forming reactions such as DCC coupling, azide coupling, mixed anhydride Eynthesis, or any other coupling procedure familiar to one 6killed in the art.
Aniline derivatives (63) will undergo reductive animation with aldehydes and ketones to form secondary amines (74). Thus the aniline is first stirred with the carbonyl compound in the presence of a dehydration catalyst 6uch as molecular sieves or p-toluenesulfonic acid. Afterwards the resultant imine is reduced to the amine with a borohydride reducing agent 6uch as sodium cyanoborohydride or sodium boro~ydride.
Standard catalytic hydrogenation reagents such as hydrogen and palladium/carbon can also be employed.
-51 1 3340q~
Alternatively, aniline (63) may be monoalkylated by reaction with ethyl formate followed by reduction with, for example, lithium aluminum hydride to produce the N-methyl derivative (74). Aniline6 (74) may in turn be reacted with carboxylic acid anhydrides and acid chlorides or carboxylic acids by any of the coupling procedure6 described previously to yield (73) where X= -N(CH3)C0-.
Aniline (63) or (74) or other intermediate anilines where the amino group may be located on another aromatic ring for example, al60 react with other anhydrides to make amide-carboxylic acid derivatives of formula (75). Thus, for example, maleic anhydride, 2,3-naphthalenedicarboxylic acid anhydride, and diphenic anhydride are reacted in a similar fashion to phthalic anhydride with aniline (63) or (79) to yield carboxylic acids (76), (77), and (78), respectively.
Phthalimide derivatives of aniline (63) may be made by a variety of methods, preferably by 6tirring aniline (63) with phthalic anhydride in acetic acid at a temperature betweén 20C and reflux, G. Wanag, A. Veinbergs, Ber., 75, 1558 (1942), or by 6tirring (63) with phthaloyl chloride, a base 6uch as triethylamine, and an inert solvent.
Aniline (63) may be converted into its tri-fluoromethanesulfonamide derivative or its trifluoroacetamido derivative preferably by reacting it with triflic anhydride or trifluoroacetic anhydride and a base such as triethylamine in an inert solvent ~uch as methylene chloride at -78C followed by warming to room temperature.
Compounds of 6tructure (I) where X i6 a carbon-carbon linkage which are depicted a6 (80) can be made as shown in Scheme 14.
Scheme 1 4 1 3 3 4 0 9 ~
R ;;~ ~ R~ R6lN, ~Q
~/ogenation Y=Br, Cl Sch~me 14 (Cont'~ 334092 Cl H3 R13 85 I~LI
d) ~
COOH N o R / t-Bu, etc.
~OCH3 ~OCH3 [~ OH
Equation a) illustrates that the biphenyl compounds (80) can be prepared by alkylation of imidazole (1) with the appropriate halomethylbiphenyl compound (79) by the general procedure described in Scheme 1.
The requisite halomethylbiphenyl intermediates (79) are prepared by Ullman Coupling of I81) and (~2) as described in 'IOrganic Reactions", 2, 6 (1944) to provide intermediates (83), which are in turn halogenated.
Halogenation can be accomplished by refluxing (83) in an inert solvent such as carbon tetrachloride for 1-6 hours in the presence of a N-halosuccinimide and an initiator such as azobisisobutyronitrile (equation b).
As shown in equation c), derivatives of intermediate (83) in which R13 is at the 2' position (~) can also be prepared by the method described in 54 l 334092 J. Orq. Chem., 41, 1320 (1976), that i6 Diel6-Alder addition of a 1,3-butadiene to a styrene (84) followed by aromatization of intermediate (85).
Alternatively, the 6ub6tituted biphenyl precur60r~ (83; where R = COOH) and their e6ters (89) can be prepared a6 illu6trated in equation d), which involve6 oxazoline compound6 a6 key intermediate6, A. I. Meyer6 and E. D. Mihelich, J. Am.
Chem. Soc., 97, 7383 (1975).
The 6ub6tituted biphenyl tetrazole6 (83; where ~Y
R13 = ~ SM) can be prepared from the nitrile precur60r ~(R13.CN) by the method6 de6cribed in Scheme 1, equation c) and Scheme 15, equation c).
However, a preferred method for preparing tetrazole6 i6 de6cribed in Scheme 15, equation6 a) and b). Compound6 (90) may be prepared by the 1,3-dipolar cycloaddition of trialkyltin or triphenyltin azide6 to the appropriately 6ub6tituted nitrile (B3) a6 in equation a). Alkyl i6 defined a6 normal alkyl of 1-6 carbon atom6 and cyclohexyl. An example of thi6 technique i6 de6cribed by S. Kozima, et al., J. Orqanometallic Chemi6trY~ 337 (1971). The required trialkyl or triaryltin azide6 are made from the requi6ite commercial trialkyl or triaryl tin chloride and 60dium azide. The trialkyl or triaryltin group i6 removed via acidic or ba6ic hydroly6i6 and the tetrazole can be protected with the trityl group by, reaction with trityl chloride and triethylamine to give (91). Bromination a6 previou61y de6cribed herein with N-bromosuccinimide and dibenzoylperoxide afford6 compound (92). Alkylation of (1) with the appropriately 6ub6tituted benzyl halide u6ing condition6 previou61y de6cribed followed by deprotection of the trityl group via hydroly6i6 1 33409~
affords ( _; R13 = tetrazole). Other protecting groups 6uch a~ p-nitrobenzyl and l-ethoxyethyl can be used instead of the trityl group to protect the tetrazole moiety. These groups as well as the trityl group can be introduced and removed by procedures described in Greene, Protective GrouPs in Orqanic SYnthesis~ Wiley-Interscience, (1980).
Scheme 15 CH~
Sn(R)3N3 'Sn(R)3 83 (R13=CN) 90 R = alkyl of 1 to 6 carbon atoms, phenyl 1);~
2) (PH)3CCl, TE~
c~3 a~2Br 2 5 ei~ N C(Phenyl)3 ~ C(Phenyl)3 ~N N95, D90 ~N
~v Scheme 15 (continued) l 3 3 4 0 9 2 .: N~ R3 R N 1)~ NaOEt R N N=N
H 2) Depro~ection ~H
80, (R13=tetrazole) c) 10 NH"CI ~ N ~
~,CN D~F [~ H,N
1 33409~
Compounds of structure 93-95 where X ls an -O-, -S-, or -N- linkage can be prepared as shown ln Scheme 16 by alkylatlon of lmldazole (1) with the appropriate benzyl halide (96).
Scheme 16 CH2Br ~-X
N~8 ~ - R13 1 j~ R7 96 ~--X
~ I
93; X=O ~--R13 94; X=S
~; X- N R26 .... .. . .
;
Scheme 16 (continued) 1 3340q2 b) f Hal CH3 97-100 ~~ CO2H
97; X=O / 101-104 ~; X=S
99; X=NH
100; X=NR26(R26~H) CH3 ~ CH2Hal ~X ~ ~X
1~ CO2CH3 [~ CO2H
109; X=O
~; X=S
111; X=NH
112; X=NR26 (R26;tH) -sg 1 3340~2 The halomethyldiphenyl ether tlO9) employed as an alkylating agent in the pre6ent invention is prepared as shown in equation b). An Ullman ether condensation of the phenol (97) and a halobenzoic acid S as de6cribed in Russian Chc-ical Revle~s, 43, 679 (1974) provides the intermediate acid (101). ~he conver6ion of llOl) into (109) ~s accompli6hed by esterification wit~ diazomethane to afford (105) followed by haloqenation employing the procedure used in the preparation of (79). The diphenylsulfide (110) and the diphenylamine (111) can be prepared from the appropriate thiophenol (98) or aniline (99) by thi6 procedure.
The tertiary diphenylamine (112) can be prepared from the secondary aniline (100) by the above procedure. Alternatively (107) can be alkylated by one of the following procedures: 1) direct alkylation of (~3) with R26L where L is a leaving group such as a halogen or to6ylate employing phase-transfer conditions and ultrasound as described ~n Tetrahedron Letters, 24, 5907 (1983), 2) treatment of (107) with 1-1.5 equivalents of an appropriate aldehyde and 0.5-5.0 equivalents of sodium cyanoborohydride in a solvent such as methanol at 25C at a pH of 3-6 for 1-24 hours, or 3) reductive amination of (~) employing an appropriate carboxylic acid and sodium borohydride as described in J. Am. Chem. Soc., 96, 7812 (1974). ~he tertiary amine (108) is t~en halogenated by the procedure previously described to qive (112).
Scheme 17 l 3340 9 2 ~R7 --R13 ~0 base ~R13 114; R13=2-Co2CH3, X=halide 1 15; R13=2-Co2CH3, X=H
N _j~R8 113; R13=2-Co2CH3 ~0 [~CO2H
x Compound6 of 6tructure (73) where X i6 -C0- are prepared a6 6hown in Scheme 17 by alkylation of imidazole (1) with the requi6ite benzoylbenzyl halide6. For example, e6ter6 (113) where R13 i6 2-C02CH3 are prepared by alkylation of imidazole (1) with carbomethoxybenzoyl benzyl halide (114).
E6ter (113) may be hydrolyzed to the corre6ponding carboxylic acid (116) by a variety of method6 including hydroly6i6 with a ba6e 6uch as 60dium hydroxide or pota66ium hydroxide in an alcoholic aqueou6 solvent 6uch a6 methanol~H20 at a temperature from 20C to the reflux temperature of the 601vent.
Carboalkoxybenzoylbenzyl halide6 (114) are prepared by benzylic halogenation of the corre6pondinq toluoylbenzene precur60r by a variety of method6 previou61y de6cribed herein. For example, methyl 2-(4-methylbenzoyl)benzoate (115) can be refluxed for 2-48 hour6 with N-bromo6uccinimide, benzoyl peroxide and carbon tetrachloride to effect benzylic bromination.
Scheme 18 l 334092 R6 l N~ R6 l N~ R l=~ R7 ~N-OR28 ~50 ~fNNHR27 ~ R13 ~ ~ R13 117 Rl3 118 [H] ~ooRR29o R13_~ 3 R6 l N~ ~ [H]R6 l N~ N ~ g8 ~OH ~ oCRl7 ~3_ R13~ R13 ~, R13 121 N _~ 122 ,1~ R7 R6 N~
~oR14 , - ~
63 1 3340~2 A6 6hown in Scheme 18 the toluoyl ketone6 (73:
where X=CO) may be further transformed into a variety of ketone derivative6 including compound6 where ~ i6 NR25 R290 oR30 OCOR OR
.. \~ . .
-C- , -C- , -CH , and -C-Reaction of ketone (73a) with a hydroxylamine or an appropriately 6ubstituted hydrazine will give the - re~ui6ite oxime6 (117) and hydrazones (118). ~eaction with alcohol6 in the pre6ence of an acidic catalyst with removal of water will qive ketal6 lll9).
Reduction, with lithium aluminum hydride, a metal borohydride, zinc/acetic acid or catalytic hydrogenation will give the corresponaing alcohol (120) or fully reduced methylene compound ~121) The6e alcohol6 may be acylated by a variety of anhydride6 or acid halide6 in the pre6ence of a base with or without 601vent to give the corre6ponding e6ter6 (122). The alcohol6 (120) may be converted into their corre6ponding ether6 (123) by reaction of the metal alkoxide with an alkyl halide, me6ylate or to6ylate in the appropriate 601Yent or by treatment with a mineral acid in an alcoholic 601vent, or by reaction of the alcohol with diazomethane G. Hilgetag and A. Martini, ~Preparative Organic Chemi6try~, John Wiley, New York, 355-368 (1972).
Compound6 of formula (I) where ~ iB -OCH2-, -SCH2-, and -NHCH2- are prepared a6 shown in Scheme 19.
Scheme 19 1 33409~
R N ~ R --~N~;
~¢--OR ~--OH ~¢ ~
12~; R = CH2Ph 126 127 ~ R13 125; R = CH3 N-- R 7 ~ R7 R6~N~
--SCH2Ph ~¢--SH
~¢ ~ reduotiveamination ~--HN
I 3340~
As illust~ated in Scheme 19, equation a, hydrolysi6 of benzyl ether (124) or methyl ether (125) a~fords hydroxy compound (126~ which can be alkylated with the a~propriate benzyl halide to give (127). In the case of the methyl ether6 (125), the hydroly6i6 step can be efected by heating the ether at tempera-ture6 of 50-150C for 1-10 hour6 in 20-60% hydrobromic acid, or heating at 50-90C in acetonitrile with 1-5 equivalent6 of trimethyl6ilyl iodide for 10-50 hour6 Lollowed by treatment with water. Hydrolysi6 can also be carried out by treatment with 1-2 equivalent6 of boron tribromide in methylene chloride at 10-30C for 1-10 hour6 followed by treatment with water, or by treatment with an acid 6uch a6 aluminum chloride and 3-30 equivalent6 of a 6ulfur-containing compound 6uch as thiophenol, ethanedithiol, or dimethyl di6ulfide in methylene chloride at 0-30C for l-Z0 hour6 fol-lowed by treatment with water. For compound (124), hydrolysis can be accomplished by refluxing in trifluoroacetic acid for 0.2-1 hour6 or by catalytic hydrogenoly6i6 in the presence of a 6uitable catalyst such as 10% palladium on carbon. Deprotonation of (126) with a base, 6uch a6 60dium methoxide, 60dium hydride or the like in a 601vent 6uch a6 dimethyl-formamide or dimethylsulfoxide at room temperaturefollowed by alkylation with an appropriate benzyl halide at 25C for 2-20 hour6 afford6 ether6 of formula (127), as 6hown in equation a.
The 6ulfide (129) can be prepared from the thiophenol (45) by the procedure described above to prepare the ether (127) from the phenol (126). The thiophenol (45) can be prepared for example by treatment o~ the benzylsul~ide (128) with 60dium in liquid ammonia.
The amine (130) can be prepared as shown in equation c, from the aniline (63), itself available from reduction of the corresponding p-nitro compound (3a) which has previously been described. The reductive amination can be carried out by the same procedure as described in Scheme 13 for the preparation of compound (74).
Compounds of Formula (I) where the X linkage is -CH=CH-, -CH2CH2-, and are prepared as shown in Scheme ~Q -Scheme ~0 ~ PPh3 1_RR7 ~ R13 ~ R61Nj --CHO 131 ~3 N .R8 132 R6J~N~ RR7 X' 67 I 33409~
The ci6 or tran6 stilbene (132) can be obtained by employing a Wittig reaction between-the aldehyde (57) and the pho6phorane (131).
The 6tilbene (132) can readily be converted to the 6aturated derivative (133) for example by catalytic hydrogenation employing a heterogeneou6 cataly6t 6uch a6 palladium/carbon or platinum/carbon or alternatively with a homogeneou6 catalyst such a6 tri~triphenylpho6-phine rhodium chloride. The reduction ~6 performed in a 601vent such as benzene, tetrahydrofuran or ethanol at 25C under 1-3 atmo6pheres of hydrogen for 1-24 hour 6 .
The cyclopropane (134) can be prepared by treating the stilbene (132) with the Simmons-Smith reagent as de~cribed in J. Am. Chem. Soc., 81, 4256 (1959), or by treating (132) with methylene diiodide and copper powder as described in J. Am. Chem. Soc., 101, 2139 (1979), or by treatment with the iron-containing methylene-tran6fer reagent described in J. Am. Chem. Soc., 101, 6473 (1979).
The preparation of compound6 of formula (I) where X i6 -CF2CH2-, -CF.CH-, -CH~CF-, -CF.CF- and -CF2CF2- are depicted in Scheme 21.
Scheme 21 1 334 0 92 a) Ar8CH2Arl + Et2NSF3. CH2C12 ~ ArCF2CH2Ar ~35 \ / 136 ~ \~HF H+ ~1 0 ArCF= CHAr .~
b )ArCH2CAr + Et2NsF3 CH2C12 ArCH2CF2 138 \ / 139 ~,THF, H ~,/
ArCH= CFAr OOH
c)ArCCHArl + Et2NSF3 H2C12 ~ ArCF2CHFAr +
25141 \TIIF,H /A1203 142 ArCF = CFArl l43 d) A CC~l + Et NS~ ArCF2CF2Ar , ~v' . ~
Vinylene fluoride6 (137) and (140) can be pre-pared by reaction of SF4 or Et2NSF3 (DAST) with the appropriate ketone (135) or (138) in which Ar bears a methyl group convertible to a benzylic halide suitable for attachment to an imidazole nitrogen, and Ar' bear6 a cyano, nitro, e6ter, or other suitable group which can be ~ubsequently converted to CO2H, NHSO2CF3, etc.
The initially formed difluroethylene (136) and (139) can be formed in a non-polar solvent such as methylene chloride and sub6equently converted to the vinylene fluoride by means of alumina, or converted directly into the un6aturated fluoride by running the reaction in a polar sol~ent such a6 tetrahydrofuran, diglyme or N-methylpyrrolidone in the presence of mineral acid.
[Equations a and b]. Experimental details of such procedures are found in D.R. Strobach and G.A. Boswell, J. Orq. Chem., 36, B18 (1971): G.A. Boswell, U.S.
Patent6 3,413,321 (1968) and 4,212,515 (1980).
As 6hown in equation c an appropriate benzoin (141) may be 6imilarly converted to the corre6ponding 1,2-difluorostilbene (143). Likewise as shown in equation d an appropriate benzil (144) can be converted to a tetrafluorodiarylethylene (145) using DAST or SF4. Experimental detail6 are described in M.E.
Christy, et al., J. Med. Chem., 20, (3), 421-430, (1977).
Compound6 of formula 1 where X = -CON-, -CH2O-, -CH25-, -CH2NH-, can be made as 6hown in Scheme 22.
Scheme 22 1 334092 N-- R87 HN--ArR13--P N /R87 N-- R87 )R6--~N~ DCC, CH~CI7~ R6~N~ deprotect~n R61~ ~ R
HN--ArR13 ~q R23 ~ R23 ~C2Hp ,TsCI, pyr ~CON-ArR13-P CONArR13 P = protecting group (if necessary) ArR13 _ ~, ~ [~
~CO Me ~CH20H ~CH20Ts N--~ R7 K2CO3, DMF deprotection R6 N~
1~; HO-Ar-R13-p ~
153; HS-Ar-R13-P l~`XArR13 146; H2N-Ar-R13-P
154; X= -CH20-155; X= -CH2S-156; X= -CH2NH-As previously described, acid (10) can be made by alkylating the appropriate imidazole with methyl 4-chloromethylbenzoate in the presence of a base 6uch as potassium carbonate in a polar solvent 6uch a~
dimethylformamide followed by hydroly~i6 of the resulting ester. Compound (10) can be converted to (148) by reaction with the requi6ite amine (146) (R13 may need to be protected and 6ub6equently deprotected) and dicyclohexyl carbodiimide (DCC) in methylene chloride tJ. R. Beek, et al., J. Am. Chem. Soc, 90, 4706 (1968)~ or by reaction with to6yl chloride in pyridine tJ. H. Brew6ter and C. J. Ciotti, Jr., J. Am.
Chem. Soc., 77, 6214 (1955)]. Yet another proce66 involve6 conversion of carboxylic acid (10) to it6 acid chloride with, for example, thionyl chloride ollowed by reaction with the amine in aqueou6 base (Schotten-Baumann condition6) or in an organic 601vent in the pre6ence of an acid 6cavenger 6uch a6 NaHC03, pyridine or triethylamine, or by other procedure~
known to form an amide bond between an aromatic acid and an amine.
The compounds where X= -CH20-, -CH2S-, and -CH2NH2- can be made a6 6hown in pathway b. The ester (149) i6 reduced with a reducing agent 6uch a6 lithium aluminum hydride in an inert 601vent to form the alcohol (150) which can then be reacted with to6yl chloride in pyridine to form tosylate (151), which i6 in turn reacted in the pre6ence of ba6e with a corre6ponding-phenol (152) thiophenol (153), or aniline (~46: where R =H) to form compound6 (154), (155) or (156). Again thi6 may require that R13 be protected with a ~uitable protecting group, however modification6 necessary because of 6pecific functional groups are under6tood to be incorporated by one 6killed in the art of organic ~ynthesi6.
72 1 3~4~q 2 Alternatively, the alcohol (150) can be con-verted to the corresponding halide with SOC12, (COCl)2, etc, and the resulting halide can then be reacted with a phenol, thiophenol or aniline in the presence of base to $or~ the desired compound, where ~ i~
-CH2O-, -CH2S-, -CH2NH- respectively.
S cheme ~ 3 R23HN~ 1 3 3 4 0 9 2 a) N ~RR87 R1158, R N~
Base ~S~02 ~ ~RR87 CISO2~ N~R 7 b) R6N~ R13 1 ~
160 W~ N R23 N H R23 Base SO2 solvent Rl 8-.
- 1 3340~2 Compound6 of Formula (I) where X= -S02NR
and -NR23So2- may be prepared a6 shown in Scheme 23. A6 6hown in equation a, 6ulfonylchloride derivative (157) can be reacted with aniline derivative (158) in a solvent in the pre6ence of an acid 6cavenger 6uch as ~odium bicarbonate, triethy~a~ine or pyridine or under Schotten-Baumann like conditions to give (159). 5ulfonylchloride derivative (157) can be obtained by sulfonation of the corre6ponding benzyl derivative a~ de6cribed earlier, followed by reaction with PC15 or POC13. Likewi6e, aniline (74) may be reacted in the ~ame manner a~
de6cribed above with 6ulfonylchloride derivative (160) to give (161).
Scheme 24 6how6 the preparation of furan analog6 of the biphenyl compound6 (80). Thu6, a-ketoe6ter (162), W. Wierenga and H. I. Skulnick, J. Orq. Chem., 44, 310 (1979), or the corre6ponding nitrile (E.CN) can be ea6ily alkylated via 6tandard procedure6 already mentioned by an alkyl bromide derivative to give (163). The alkene moiety of (163) can be 6ub6equently cleaved by oxidation, for example, with 06mium tetroxide, Fie6er and Fie6er, V.l, p. 812 (Lemieux-John60n oxidation) to yield dicarbonyl-containing compound (164). Cyclization in mineralacid6, acidic ion-exchange re6in, POC13/pyridine, or trifluoroacetic anhydride with a catalytic amount of trifluoroacetic acid yield6 furan (165: Z.O).
Reaction of (164) with P4Slo, for example, will yield the corre6ponding thiophene (165; Z.S).
aeactiOn of (164) with an amine in refluxing benzene, with azeotropic removal of water or by u6ing ~olecular 6ieve6 to ab60rb the water will yield the corre6ponding pyrrole (165; Z-NR ). Compound6 (166) may be prepared from (165) by 6tandard procedure6 already de6cribed.
Scheme ~4 l 3 3 4 09 2 (Cl, 1, OTs, OMs, etc.~
E oS~ E
~R11 1~ E= CO2Me or CN R11 ~E ~ ~
Rll R11 O~ E
165 q~ R 11 E = CO2Me, CN R11 Z=O,S,NR1' N--~R7 ~OOH) (1 ~N ) R
166 Z = O, S, NR
t6 1 33409~
Compound6 wherein a methylene group is inserted between the terminal aromatic ring and the acidic functionality may be prepared a6 shown in Scheme 25, equation a). Thu6 reduction of e6ter (167) with, for example, lithium aluminum hydride, give6 alcohol (168). Conver6ion of (16~) to the chloride (169) via thionyl chloride followed by reaction with cyanide anion a6 previou61y de6cribed yield6 nitrile (170).
Compound (170) may be hydrolyzed to carboxylic acid (171) by method6 already de6cribed or reacted with a hydrazoic acid equivalent to produce tetrazole (172).
Compound6 wherein R i6 a trifluoromethyl6ul-fonyl hydrazide acidic functional group were prepared by the procedure de6cribed in equation b). That i6, conver6ion of e6ter (167) to the hydrazide (173) by standard hydrazinoly6i6 followed by reaction with triflic anhydride afford6 hydrazide6 (174).
Scheme 25 1 3 3 4 0 9 2 R6,l~ ~ R 1~ ~
~X C02Me ~X CH2oH
R61 ~ R6 1N , R
~ ~ ~ CHzCl (OTs, OMs, 3r, etc.~
~ ~
R61~ ~ R R6 ~ N ~
~ COOH ~ X ~ ~
R6 J~N~ R7 N ~ R8 ~ X O NH-NHZ ~ NHNHSOZCH3 173 ~ 174 i~ ~r .
- 1 3.j40~2 The 6yntheses of compound6 wherein Rl i6 sub~tituted and un6ubstituted l,2,3-triazole6 are described in Scheme 26. Thus reduction of e6ter (175) with a reducing agent 6uch a6 lithium aluminum hydride or diisobutylaluminum hydride give6 alcohol (176).
Oxidat-ion with MnO2 or pyridinium chlorochromate converts (176) into aldehyde (177). Nitroethylene derivative ~178) i6 prepared by conden6ation of aldehyde (177) with nitromethane in the presence of a catalyst, R. M. Letcher and M. P. Samme6, J. Chem.
Ed., 62, 262 (1985). Reaction of (178) with 60dium azide produce6 the 1,2,3-triazole (179), (N. S.
Zefirov, et al., J. Chem. Soc. Chem. Comm., 1001 (1971)) which may be transformed via procedure6 already de6cribed into product (180).
Aldehyde (177) can al60 be converted into sub6tituted 1,2,3-triazole6 (183) via the 6ulfone (181), G. Beck, D. Gunther, Chem. Ber., 106, 2758 (1973), followed by reaction with sodium azide to give the 1,2,3-triazole (182). Subsequent 6tandard manipulations lead to 1,2,3-triazole6 (183) where E=CN
and C02Rll. The nitrotriazole (183: E.N02) may be synthe6ized from the unprotected triazole (179;
P=H) via nitration, R. H~ttel, et al., Chem. Ber., 88, 1586 (1955), C. L. Habraken and P. Cohen-Fernande6 J. Chem. Soc., 37 (1972), or from bromonitroethylene derivative (184), G. Kh. Khi6amutdinov, et al., Zh.
Orq. Khim., 11, 2445 (1975), by reaction with 60dium azide.
A variety of protecting group6 may be u6ed in the manipulation of the above triazole6, among6t which i6 the trityl group. Thi6 group ~ay be ea6ily attached by reaction of the triazole with triphenylmethyl bromide or chloride in an inert solvent such a~ methylene chloride in the pre6ence of an acid 6cavenger such a~ triethyl amine. The trityl -group may be later removed by stirring or refluxing in an acidic medium 6uch a6 trifluoroacetic acid/water.
HCl in methylene chloride, or acetic acid/water. The trityl group may al60 be hydrogenolyzed u6ing a noble metal catalyst 6uch a6 palladium and hydrogen.
Scheme 26 1 3340q2 R=CH OH X~
177: R = CHO . NO2 1 ) NaN3 2) protecbion \~X~ ~ Br \~
1) NaN3 1) NaN3 2) protecbon 2) protection ~I
X~ ~X~
1 82 ~ N R7 R6lNi~ N= R~ P
~~ E = cO2R11, CH, N2 P = protecting group The 6ynthe6i6 of trifluoromethyl-1,2,4-triazole6 (190) i6 depicted in Scheme 27. Acid chloride (186) i~ converted to amide (187) u6ing 6tandard procedure6 familiar to one 6killed in the art. A preferred protecting group i6 the 2-propionitrile group (PzCH2CH2CN). Thu~ (187; P=CH2CH2CN) can be 6ynthe6ized from (186) and *-aminopropionitrile under Schotten-Baumann like condition6, using aqueou6 ba6e in an organic 601vent to help solubilize (186) and (187). Amide (187) i8 converted to amidrazone (188) by reaction with PC15 or pho6gene to make an iminoyl chloride which then in turn i6 reacted with exce66 hydrazine. Amidrazone (188) i6 cyclized to the trifluoromethyl-1,2,4-triazole (189) with trifluoroacetic anhydride and then converted to 190 via bromination, alkylation and deprotection a6 previou61y de6cribed.
S cheme 2 7 1 3340~2 P = PROTECTING GROUP
,0, ,0, ~ ~ Fl7 ~,F3C-O-CCF3 R6 N~
N~ ~ pN
~r -Pertinent R group6 may be variou61y intro-duced by many procedure~ including tho6e de6cribed in Scheme 28 which de6cribe6 imidazole con6tcuction.
The R6 group~ 60 introduced may 6tand unchanged or may be further elaborated if appropriately function-alized, according to method6 familiar to tho6e 6killed in the art 6uch a6 are illu~trated in Scheme 28.
Scheme 28 1 334092 NH OEt HO~~OEt H2N~OCH3 1)EtOH ~
OCH32) aq HCI J H
HO
1 ) Protect/
~2) TsCI
~9 R5(CH2)mSH ~ R5(CH2)moH N~3 R5(CH2)mS R'O NaH R5(cH2)mo 194 R5(CH2)mBr 197 R = CPh3, S02Ph, CH3CHOC2H5 :L~2; R' = H ~; R' = Ts PDC
~3 R5(CH2)mNH2 ~Ph3P=CHR' N~3 R NaCNBH3 N J R
R5(CH2)mNH CHO R R~ ~
1 33409~
B L A N K
P A G E:
-1 33409~
B L A N K
P A G E
1 3340q2 - The 2-alkenylimidazole6 (?ol) can be prepared by bromination of the 2-alkylimidazole6 (199) followed by elimination of hydrogen bromide. The bromization i6 preferably accompli6hed by W-irradiation for 1-4 hour6 of imadoyole (199) and N-bromosuccinimide, in an inert 601vent, 6uch a6 carbon tetrachloride at 25C.
Treatment of the intermediate bromide (?) with a ba6e, 6uch a~ DBU, triethylamine, or pota66ium t-butoxide, afford6 the tran6 2-alkenylimidazole6 (201). Ci6 alkenyl derivative6 (?03) are prepared from the tran6 alkenyl compound6 by treatment with 06mium tetroxide and 60dium periodate to afford aldehyde6 (202) followed by Wittig reaction.
_- 88 Scheme ~ 9 R~ ~ R bromination ~--~ N;~
-J /v\J
~/-HBr R~N--~RR87 ~ ~ R7 OSO4 (cat) H
R1 NalO4 R3 R2 ~N~ ~/\= PPh3 /v\J
~Q~
R = alkyl, cycloalkyi ..~
89 1 3340q 2 Alternatively, R g~oups may be introduced by metallation of a protected imidazole or protected 2-methylimidazole followed by addition of an appro-priate electrophile a6 illu6t~ated in Scheme 30, equation6 a) and b). The product6 (alcohol6, e6ter6, halide6, aldehyde6, alkyl6) are 6uitable for further elaboration by method6 familiar to tho6e 6killed in the art. Metallation of imidazole6 i6 de6cribed in K.L. Xirk, J. Orq. Chem., 43, 4381 (1978); R.J.
Sundberg, J. Het. Chem., 14, 517 (1977): J.V. Hay et al., J. Orq. Chem., 38, 4379 (1973): B. Iddon, HeterocYcle6~ 23, 417 (1985).
Conden6ation of 2-methylimidazole and appropriate electrophile6 (equation b) with catalytic acid or base a6 de6cribed in A.R. Katritzky (~d.), "Comprehen6ive Heterocyclic Chemi6try", Vol. 5, p. 431, Perqamon Pre66, N.Y., 1984 afford6 product6 wherein R6 i6 alkenyl which are 6uitable for further elaboration.
~ - 9o Scheme 30 ; 33409~
a) <~ N~ 1) R6x ~ 6R~N~
R R 2)H+ H
~L ~ (where R7=R3=H) R= CPh3, SO2Ph b)~N~ nBuLi ~ <~ 2) H+ N
206 207 2Q~
1 ) RCHO
\ ZnCI2 \2) H+
\~ N~
~N
R~ H
~Q~
~ 91 1 334092 Various 2-substituted imidazoles can be prepar-ed by reaction of a protected 2-trimethylsilylimi~7ole with a suitable electrophile by the method described by F.H. Pinkerton and S.F. Thames, J. Het. Chem., 9, 67 (1972), which can be fkrther elaborated as desired.
Alternatively, R6 may also be introduced by nickel catalyzed cross-coupling of Grignard reagents with 2-(methylthio)imidazoles (Scheme ~1) as described by E. Wenkert and T.W. Ferreira, J. Chem. Soc., Chem.
Commun., 840, (1982); E. Wenkert et al., J. Chem.
Soc., Chem. Commun., 637, (1979); and H. SllE~lra and H. Takei, Bull. Chem. Soc. Japan, ~ 664 (1985).
The 2-(methylthio)imidazoles can be produced by the procedure described in German Patent No. 2,618,370 and the references cited therein.
Scheme 31 KNCS + RN ICHcH(OcH3)2 aq HCI~ HS~ CH31 CH3S ~ ~ R8 R6MgCi , R6 ~ ~ R8 R (Ph3P)2NiCI2 R
3 or 2~ NiCI2 (dppp) 213 , _ 1 33409~
A6 shown in Scheme6 32-35, elaboration of R8 can be accompli6hed by procedure6 de6cribed in Scheme6 3, 28 and 30b and by chain exten6ion reaction6 familiar to tho6e 6killed in the art in which R bear6 a reac-tive terminal functional group, e.g. -OH, halogen, -CHO, -C02R, -C02H, -CH~CH2,-NH2, -N02, -CN, -C.NH, OR
etc., or by degradation reaction6 ~uch a6 conversion of an e6ter to an acid or an al~ene to an aldehyde.
Specifically, the hydroxymethyl group can be activated for the di6placement reaction by reacting with thionyl chloride, PC15 or with carbon tetra-chloride/triphenylpho6phine to form a corre~ponding chloro derivative. By a 6imilar reaction bromo and iodo derivative6 can be obtained. The hydroxymethyl group can al60 be activated by forming the corre-6ponding p-toluene6ulfonate, methane6ulfonate and trifluoromethane 6ulfonate derivative6. The hydroxyl group can be converted to it6 corre6ponding fluoro compound by variou6 fluorinating agent6 6uch a6 DAST
a6 6hown in Scheme 32.
-. Sche,m2 32 R7 ~7 R 6~ N~OH 2 2 (CH2)r (CH2)r Rl~ Rl~R3 ~,, , _' o 15 ~ ZnI
6~<~50'CH3 eOH , R61N~ SH
20(CH2)r (CH2)r R 1~3 R1~3 215 ` 216 ., 94 1 3~4092 Also as 6hown in Scheme 32, the hydroxyl group can be converted to thiolacetic acid derivative (215), J. Y. Gauthier, Tet. Lett., 15 (1986), and to thiol derivative (216) by subsequent hydroly6i6.
l~he hydroxymethyl group on compound (17) can be readily oxidized to an aldehyde group by mean6 of manganese dioxide or ceric ammonium nitrate. The aldehyde gcoup will undergo chain exten6ion reaction6 such as the Wittig and Wittig-Horner reactions and enter into typical carbon-carbon bond forming reactions with Grignard and lithium reagent6 as well as with compound6 bearing activated methylene group6.
Alternatively, the hydroxymethyl group can be oxidized directly to an acid functionality which can in turn be converted to ester and amide derivatives. The ester6 and amides can be prepared directly from the aldehyde6 by manganese dioxide oxidation in the pre6ence of 60dium cyanide and an alcohol or amine, J. Am. Chem.
S_c., 90, 5616 (1968) and J. Chem. Soc. (C), 2355 (1971).
As shown in Scheme 33, the chlorine on compound (25) can be displaced by the anion of dialkyl malonate to give the corresponding malonate derivative (217).
The saponification of (217) with NaOH (or ~OH) give6 the corresponding diacid which can be decarboxylated to give the corre6ponding propionic acid derivative (218) by heating to 120C. Alternatively, (218) can be directly obtained by re~luxing (217) with a mineral acid such as HCl or sulfuric acid. The free acid (218) can be esterified by heating in a medium of the variou6 alcohols and a catalytic amount of mineral acids 6uch as HCl or sulfuric acid to give the corre6ponding esters (Zl9). Alternatively the esters can be obtained by reacting the free acid (21B) and the corresponding alcohols in the presence of coupling reagents ;uch as DDQ or EEDQ. A .s~mil~r reaction with various mono-substituted and disubstituted amines pro-duces the corresponding amldes (220). A similar reac-tion with various mercaptans produces the corresponding thioesters.
Scheme 33 R6l~ M0 ~< l~
N COOR R~ N COOR 1)NaOH(KOH) 2~
(CH2), R170H/H+ R61,~CooR17 R2 R3 Rl ~2)r ~ \R18R19NH R2 R3 R6~ CONR18R~9 (cH2)r R1 ~
~Q
A~ ~hown in Scheme 34, the chloro group on ~?5) can be displaced by the ~odium 6alt or pota66ium salt o the alkyl, aryl or arylalkyl mercaptan6 to give the corresponding ~ulfide derivatives (221). The amine derivative (222) can be obtained by treating (?5) with ammonia or with the corresponding mono-6ub~tituted amines. Alternatively, the chloro group may be di6-placed by 60dium azide to give an azide intermediate which upon reduction with H2 over a noble metal cata-lyst or with a reducing agent 6uch a6 chromou6 chloride(W. K. Warburton, J. Chem. Soc., 2651 (1961)) yield6 (222) where R and R are hydrogen. Thi6 amine can be 6ub6equently alkylated with alkyl halide6, or reductively alkylated with aldehyde6 and ketone6 to give alkyl derivative6 of (222). The amine6 (?22) are converted to the corre6ponding carbamate6 (?24), 6ulfonamide6 (225), amides (226) or urea6 (?27) by 6tandard procedure6 illustrated in Scheme 34 and familiar to one 6killed in the art. The nitro compound (223) can be obtained by the treatment of (25) with 60dium nitrite or pota66ium nitrite. The nitrate (228) may be ~ynthesized by treatment Of (?5) with AgN03, A. F. Ferri6, et al., J. Am. Chem. Soc., 75, 4078 (1953).
Scheme 34 1 3 3 4 ~ ~ 2 R6 l~CI R6 _~ONO2 (cH2)r AgNO3 (cH2)r R1 R~ R3 Rl R~R3 \ 22 M~ R11NH2 \~N2 R6--Y~SR R6 ~NHRll R N~
R1--2~)3 R1 RÇ~ 3 R1 R2~ 3 O
~ R1SO2C OH R10~ R7 N~NR oR10 ~N--c _ R10 I NR1 1 1CR1o O N O (CH2)r R1 ~z~ R3 Rt R~2/~3 R1 R`/~R3 . ~ ~
-- _ .
Scheme 34 (Con t) 1 3 3 4 0 9 2 5R10-N=c=o ` N;~ R11 0 Hl (cH2)r R1 ~
Scheme 35 R7 ~R6 ~ ~ (cH2)n R16 25z ~ 3~ (where R16 = alkyl, (R = pyndyl)cycloalkyl, -(CH2)pC6H5) The compounds of this invention and their prepa-ration can be understood further by the following exam-ples, which do not constitute a limitation of the invention. In these examples, unless otherwise indicated, all temperatures are in desrees centi_rade and parts and percentases are by weight.
~ . ~
99 1 33409~
Example 1 PART A: Preparation of 2-Butyl-4-chloro-1-(q-cyanobenzYl~-5-hydroxymethylimidazole To a 601ution of 2-butyl-4-chloro-5-~ydroxy-methylimidazole (prepared a6 de6cribed in U.S.
4,355,040; 3.56 g, 40 mmol, 1 eq) in 300 mL methanol was added dropwise a fre~hly prepared 60dium methoxide ~olution (0.92 g Na, 40 mmol, 1 eg, in 30 mL MeOH).
After 6tirring for O.S hour6, the methanol was removed in vacuo and the re~ultant glas6 wa6 di6601ved in 100 mL DMF. To thi6 mixture wa6 added a 601ution of a-bromo-~-tolunitrile (8.60 g, 44 mmol, 1.1 eq) in DM~ and the entire content6 stirred overnight under N2 at room temperature. The ~olvent wa6 then removed in vacuo and the re~idue di6601ved in 300 mL ethyl acetate and 300 mL H20. The layer6 were 6eparated and the aqueou6 layer wa6 extracted twice with 300 mL
portions of ethyl acetate. The organic layer6 were dried and evaporated and the crude product fla6h chromatographed over 6ilica gel in 1:1 hexane/ethyl acetate to give 6.83 g of one regioi60mer a6 a white 601id; m.p. 92.5-98Ø NMR (200 MHZ,CDC13) ~
7.65 (d, 2H, J= 8Hz); 7.13 (d, 2H, J= 8Hz): 5.30 (6, 2H); 4.46 (6, 2H); 2.49 (t, 2H, J= 7Hz): 1.59 (m, 2H);
1.28 (m, 2H); 0.84 (t, 3H, J= 7Hz). Mas6 Calcd. for C16H18N30Cl: 303.1138. Found: 303.1124.
Continued elution gave 3.56 g of the 6econd regioi60mer a~ a white 601id, li6ted below a6 the fir6t entry in Table 1.
The intermediates 6hown below were prepared or could be prepared in acco~dance with the procedure described in Example 1, Part A u6ing the appropriately substituted imidazole and benzyl halide a6 6tarting material.
-R7 1 3340~2 N~
R6~N~
~3_Rl ,, Rl R6 R7 R8 MP( 10 4-CN n-butyl CH20H Cl 98.0-100.0 4-N02 n-butyl Cl 2 56.8- 59.5 4-N02 n-butyl CH2H Cl 114.5-116.5 2-CN n-butyl Cl CH20H 93.0- 95.5 PART B: Preparation of 2-Butyl-4-chloro-1-(4-cYanobenzyl)-5-cyanomethylimidazole Thionyl chloride (3.60 mL. 49 ~mol. 5 eq) was 610wly dripped into a ~olution of 2-butyl-4-chloro-1-(4-cyanobenzyl)-5-hydroxymethyl~imidazole (3.0 g, 9.9 mmol, 1 eg) in a minimum of CHC13. The mixture wa6 6tirred for 2 hour6 at room temperature after which the 601vent was removed in vacuo and the re6idue 6uspended in toluene (200 mL). The toluene wa6 removed on the rotary evaporator and thi6 procedure wa6 repeated again to remove all trace6 of thionyl chloride. The chloride wa6 then di6601ved in DMS0 (minimum to di6601ve) and added to a 601ution of sodium cyanide (2.90 g, 59 mmol, 6 eq) in DMS0 (200 mL). The 601ution wa6 6tirred overnight under N2 at room temperature after which 500 mL H20 wa6 added and the aqueou6 layer wa6 extracted three time6 with 300 mL of ethyl acetate.
The organic layer6 were dried and concentrated and the re6idue fla6h chromatographed in 4:1 hexane/ethyl acetate over 6ilica gel to give 1.62 g of a light yellow 601id; m.p. 109.5-113.0 NMR (200 MHz, CDC13) 7.70 (d, 2H, J= lOHz): 7.12 (d, 2H, J= lOHz); 3.51 101 1 3340q2 (s, ZH); 2.60 (t, 2H, J= 7Hz) 1.70 (m, 2H): 1.40 (m, 2H); 0.90 (t, 3H, J= 7Hz). Mass spectrum shows M =
312~314. Mass Calcd. for C17H17ClN4: 312.1139, Found 312.1126.
The intermed~ates shown below were prepared, or could be prepared, in accordance with the procedure described in Example 1, Part B using the appropriately substituted imidazole and benzyl balide as starting material.
R6lN~R8 ~ Rl R R R R MP(C) 20 4-CN n-butyl C 2 Cl (oil) 4-N02 n-butyl Cl 2 117.0-119 4-N02 n-butyl 2 Cl (oil) 2-CN n-butyl Cl CH2CN (oil) 3-CN n-butyl Cl 2 (oil a NMR (200 MHz, CDC13) ~ 7.66 (d, 2H, J= 7Hz);
7.12 (d, 2H, 2, J= 7Hz); 5.15 (s, 2H); 3.69 (s, 2H), 2,56 (t, 2H, J= 7Hz); 1.62 (t of t, 2H, J=
7,7Hz); 1.33 (t of q, 2H, J= 7,7Hz); 0.87 (t, 3H, J= 7Hz).
b NMR (200 MHz, CDC13) ~ 8.24 (d, 2H, J=
lOHz); 7.18 (d, 2H, J= lOHz); 5.20 (s, 2H);
3.67 (s, 2H); 2.55 (t, 2H, J= 7Hz); 1.64 (m, 2H); 1.34 (m, 2H); 0.85 (t, 3H, J= 7Hz).
102 1 3340q~
c NMR (200 MHz, CDC13) ~ 7.80 (d, lH, J=
lOHz): 7.64 (d of d, lH, J= lO,lOHz): 7.53 (d of d, lH, J= lO,lOHz); 6.74 (d, lH, J=
lOHz); 5.37 (s, 2H); 3.64 (s, 2H); 2.55 (t, 2H, J= 7Hz); 1.67 (m, 2H): 1.34 (m, 2H):
0.85 (t, 3H, J= 7Hz).
d NMR (200 MHz, CDC13) ~ 7.66 (d, lH, J=
7Hz): 7.54 (d of d, lH, J. 7,7Hz); 7.33 (~, lH); 7.25 (d, lH, J. 7Hz); 5.25 (6, 2H);
3.56 (s, 2H): 2.61 (t, 2H, J= 7Hz): 1.69 (m, 2H): 1.35 (m, 2H): 0.91 (t, 3H, J= 7Hz).
PART C: Preparation of 2-Butyl-1-(4-carboxybenzyl)-4-chloroimidazole-5-acetic acid 2-Butyl-4-chloro-1-(4-cyanobenzyl)-5-(cyano-methyl)imidazole (0.5 g) and a solution of 1:1 12 N
HCl/glacial acetic acid (10 mL) were mixed and refluxed for 6 hour~. The solvent6 were removed by rotary evaporation and the resultant solids were washed with isopropanol, and filtered. The mother liquor was flash chromatographed on silica gel in 1:1 hexane/ethyl acetate to give 60 mg of product. Further flushing of the column with isopropanol followed by preparatory TLC of the evaporated residue gave an additional 100 mg of product. NMR (200 MHz, DMS0-d6) ~ 7.90 (d, 2H, J= 8Hz); 7.12 (d, 2H, J=
8Hz); 5.30 (s, 2H); 3.08 (s, 2H); 2.50 (t, 2H, J=
7Hz); 1.49 (m, 2H); 1.24 (m, 2H); 0.79 (t, 3H, J=
7Hz). Mass. Calcd. for C13HlgClN2O4:
350.1033. Found 350.1066.
Example 2 1 3340~2 PART A: Preparation of 2-Butyl-4-chloro-1-(4-nitrobenzYl)imidazole-5-acetic acid 2-Butyl-4-chloro-5-(cyanomethyl)-1-(4-nitro-s benzyl)imidazole (7.08 g) and a 1:1 mixture of 12 N
HCl and glacial acetic acid (175 mL) were mixed and refluxed for 6 hour6. The 601vent6 were removed by rotary evaporation and water (300 mL) was then added to the residue. After a few minutes, the product precipitated and wa~ collected and dried to give 7.35 g of a solid: m.p. 207.0-210Ø NMR (200 MHz, D~SO-d6/CDC13) ~ 8.20 (d, 2H, J= lOHz): 7.22 (d, 2H, J= lOHz); 5.28 (s, 2H): 3.42 (6, 2H); 2.52 (t, 2H, J= 7Hz); 1.64 (m, 2H); 1.34 (m, 2H); 0.86 (t, 3H, J= 7Hz). Anal. Calcd. for C16H18ClN304; C, 54.63;
H, 5.16; N, 11.94. Found: C, 54.52; H, 5.05: N, 12.21.
PART B: Preparation of Methyl 2-butyl-4-chloro-1-(4-nitrobenzyl)imidazole-5-acetate 2-Butyl-4-chloro-1-(4-nitrobenzyl)imidazole-5-acetic acid (7.35 g, 20.9 mmol, leq); 3.1H HCl in dioxane (34.0 mL, 105.4 mmol, 5 eq) and 100 mL
methanol were mixed and refluxed for 7.5 ~ours. The solvents were removed by rotary evaporation and the re~idue taken up in methylene chloride and 1 N NaOH
(300 mL each). The layer~ were separated and the organic layer washed two more times with lN NaOH
(300 mL each), dried and concentrated to give 5.43 g of a light pin~ solid; m.p. 97.5-100Ø NMR (200 MHz, DMSO-d6) ~ 8.23 (d, 2H, Js 9Hz); 7.33 (d, 2H, J= 9Hz): 5.50 (~, 2H): 3.73 (6, 2H): 3.40 (s, 3H):
2.66 (t, 2H, J= 7Hz); 1.53 (m, 2H): 1.22 (m, 2H): 0.76 (t, 3H, J= 7Hz). Ma~s Calcd. for C17H20N304Cl:
365.1140. Found: 365.1158.
Methyl 2-butyl-S-chloro-1-(4-nitrobenzyl)-imidazole-5-acetate was al~o prepared by the procedure described in Example 2 Part B from 2-butyl-5-chloro-1-(4-nitrobenzyl)imidazole-5-acetic acid. NMR (200 MHz, CDC13) ~ 8.23 (d, 2H, J= lOHz); 7.20 (d, 2H, J= lOHz): 5.21 (6, 2H): 3.75 (c, 3H): 3.67 (8, 2H);
2.58 (t of t, 2H, J= 7Hz): 1.32 (q of t, 2H, J. 7Hz):
0.86 (t, 3H, J= 7Hz). Mass Calcd. for C17H20ClN304:
365.1142. Found 365.1132.
PART C: Methyl 2-butyl-4-chloro-1-(4-aminobenzyl)-imidazole-S-acetate A mixture of methyl 2-butyl-4-chloro-1-(4-nitro-benzyl)imidazole-S-acetate (S.00 g, 13.7 ~mol, 1 eq), iron (2.67 q, 47.8 ~mol, 3.5 eq), glacial ~cetic acid (5.47 mL, 95.3 mmol, 7 eq), and methanol (250 mL) wa~
refluxed for S.S hour~. The solvent was removed by rotary evaporation. The re~idue wa6 diluted with water (300 mL) and extracted five time6 with 300 mL
portions of ethyl acetate. The organic layers were dried and concentrated. The residue wa~ fla~h chromatographed in 75:25 hexane/ethyl acetate over 6ilica gel to qive 4.53 g of a golden yellow oil which crystallized after standing for several day~. NMR
(200 MHz, CDC13) ~ 6.72 (d, 2H, J= 7Hz); 6.60 (d, 2H, J= 7Hz): 4.99 (6, 2H): 3.61 (8, 3H): 3.47 (8, 2H):
2.60 (t, 2H, J= 7Hz): 1.68 (m, 2H): 1.35 (m, 2H): 0.86 (t, 3H, J= 7Hz). Mass 6pectrum showQ M~ . 335/337.
Ma~s C 1 . 17 22 3 2 335.1407.
The following intermediate~ were prepared by the procedure de~-cribed in Example 2, Part C from the corre6ponding nitro intermediates:
-N ~
R6~N~R8 ~Rl Rl R R R MP(C) 10 4-NH2 n-butyl CH2CO2CH3 Cl (oil) g-NH2 n-butyl ClOCOCH3 (oil) 4-NH2 n-butyl Cl 2 (oil) 15 a NMR (200 MHz, CDC13) ~ 6.85 (d, 2H, J=
7Hz): 6.63 (d, 2H, J= 7Hz); 4.95 (s, 2H);
3.69 (s, 3H); 2.57 (t, 2H, J= 7Hz); 1.59 (t of t, 2H, J= 7,7Hz): 1.30 ( t of q, 2H, Js 7,7Hz); 0.86 (t, 3H, J= 7Hz).
20 b NMR (200 MHz, CDC13) ~ 6.74 (d, 2H, J=
lOHz): 6.60 (d, 2H, J= 10Hz); 4.97 (s, 2H);
4.95 (s, 2H); 3.56 (t, 2H, J= 7Hz); 1.86 (s, 3H); 1.64 (t of t, 2H, J= 7,7Hz); 1.33 (t of q, 2H, J= 7,7Hz); 0.85 (t, 3H, J= 7Hz).
25 c NMR (200 MHz, CDC13) ~ 6.80 (d, 2H, J=
10Hz); 6.69 (d, 2H, J= 10Hz); 5.05 (s, 2H);
4.43 (s, 2H); 2.56 (t, 2H, J= 7Hz); 1.56 (t of t, 2H, J= 7,7Hz); 1.26 (t of q, 2H, J=
7,7Hz); 0.83 (t, 3H, J= 7Hz).
106 1 3340~2 PART D: Preparation of Methyl 2-butyl-1-t4-(2-carboxybenzamido)benzyl~-4-chloro-imidazole-5-acetate A chloroform solution (10 mL) of methyl 2-butyl-4-cbloro-1-(4-aminobenzyl)imidazole-5-acetate (500 mg, 1.5 mmol, 1 eq) wa6 mixed with a chloroform 601ution (10 mL) of p~thalic anhydride (221 mg, 1.5 mmol, 1 eq).
After five minute6 of stirring at room temperature, product began to precipitate. After 24 hour6, the product wa6 filtered, waEhed with a minimum amount of CHC13 and dried to give 400 mg of a white 601id.
After some evaporation, the mother liquor yielded an additional 220 mg of product, both of which ~ad identical melting point6: m.p. 109.5 - 112.5. NMR
(200 MHz, DMSO-d6) ~ 10.37 (S, lH): 7.85 (d, 2H, J= 8Hz): 7.71-7.50 (m, 5H): 6.96 (d, 2H, J= 10Hz):
5.12 (6, 2H): 3.60 (8, 2H): 3.49 (6, 3H): 2.55 t, 2, J= 7Hz): 1.52 (m, 2H): 1.27 (m, 2H): 0.83 (t, 3H, J=
7Hz). The carboxylic acid could be titrated with 1.000 N NaOH to form the 60dium 6alt. High re601ution ma66 6pectrum 6how6 M-18 (1066 of H20). Calcd. Ma66 for C25H26ClN3O5: 465.1455. Found: 465.1440.
ExamPle25 PART A: Preparation of 2-Butyl-5-chloro-1-(4-nitrobenzyl)imidazole-4-acetic acid 2-Butyl-5-chloro-4-cyanomethyl-1-(4-nitrobenzyl)-imidazole (4.48 g) wa6 converted to the corre6ponding carboxylic acid by the procedure de6cribed in Example 2, Part A. No product precipitated upon the addition of water (300 mL) until the pH wa6 raised to about 3 with conc. ammonium hydroxide to liberate the imid-azole from it6 HCl 6alt. The precipitated 601id6 were amorphous and ethyl acetate (5 x 300 mL) wa6 u~ed to extract the product. Tbe organic layer6 were dried -107 l 334092 and concentrated to give 3.93 g of a yellow 601id.
Recrystallization from hexane/ethyl acetate gave 3.06 g of a white solid; m.p. = 138.0-139.5. NMR (200 MHz, CDC13) ~ 8.25 (d, 2H, Jz lOHz): 7.21 (d, 2H, S J= 10Hz): 5.23 (s, 2H): 3.30 (6, 2H): 2.63 (t, 2H, J=
7Hz): 1.63 (t of t, 2H, J= 7,7Hz); 1.32 (t of q, 2H, J= 7,7Hz): 0.87 (t, 3H, J= 7Hz). Anal. Calcd. for C16H18ClN3O4: C, 54.63: H, 5.16: N, 11.94. Found: C, 54.75: H, 5.29: N, 12.14.
PART B: Preparation of Methyl 2-butyl-1-14-(2-carboxybenzamido)benzyl]-5-chloro-imidazole-4-acetate 2-Butyl-5-chloro-1-(4-nitrobenzyl)imidazole-4-acetic acid (Part A) was carried on to methyl 2-butyl-l-t4-(2-carboxybenzamido)benzyl]-5-chloroimidazole-4-acetate: m.p. 150.5-152.5 by the procedure described in Example 2. NMR (200 MHz, DMSO-d6) ~ 13.00 (bs, lH):
10.40 (6, lH), 7.87 (d, lH, J= 8Hz); 7.67 (d, 2H, J= 8Hz): 7.71-7.52 (m, 3H): 7.02 (d, 2H, J= 8Hz): 5.13 (s, 2H): 3.61 (s, 3H): 3.52 (s, 2H): 2.59 (t, 2H, J= 7Hz): 2.53 (t of t, 2H, J= 7,7Hz): 1.28 (t of q, 2H, J= 7,7Hz): 0.82 (t, 3H, J= 7Hz). Has6 Calcd. for C25H26ClN3O5-H2O: 465.1455. Found, 465.1460.
ExamPle 4 PART A: Preparation of 2-n-Butyl-4-chloro-5-methoxy-methyl-1-(4-nitrobenzYl)imidazole 2-n-butyl-4-chloro-5-hydroxymethyl-1-(4-nitrobenzyl)imidazole (10.5 g, 32.4 mmol, 1 eq), conc.
sulfuric acid (26 mL) and methanol (300 mL) were mixed and refluxed overnight. The 601vent was removed in vacuo and the re~idue taken up in water (about 300 mL). The pH was adjusted to 5 with lN NaOH and then this aqueous portion extracted with ethyl acetate (3 x 250 mL). The organic layers were collected, dried (MgS04) and the ~olvent removed in vacuo to yield 11.57 g of an amber oil. NMR (200 MHz, CDC13) ~ 8.22 (d, 2H, J= 8Hz): 7.15 (d, 2H, J= 8Hz): 5.26 (~, 2H): 4.25 (s, 2H): 3.23 (6, 3H): 2.52 (t, 2H, J-7Hz): 1.64 (t of t, 2H, J= 7,7Hz); 1.28 (t of q, 2H, J= 7,7Hz); 0.81 (t, 3H, J= 7Hz). Anal. Calcd. for C16H20ClN303-(H20)o 5: C, 55.41: H, 6.10: Cl, 10.22.
Found: C, 55.21: H, 6.22: Cl, 9.92.
PART B: Preparation of 1-(4-Aminobenzyl)-2.n-butyl-4-chloro-5-(methoxYmethyl)imidazole To a 601ution of 2-n-butyl-4-chloro-5-methoxymetbyl-1-(4-nitrobenzyl)imidazole (11.22 g) in methanol (100 mL) under N2 was carefully added 1.0 g of 10~ palladium on charcoal. Hydrogen ga6 was then bubbled through the solution for 4 bour6. The solution was filtered through Celite~ and the solvent removed in vacuo to yield 9.23 g of an amber oil. NMR (200 MHz, CDC13) ~ 7.99 (6, lH): 6.78 (d of d, 4H, J= 5,5Hz): 5.05 (8, 2H): 4.24 (6, 2H): 3.27 (6, 3H): 2.59 (t, 2H, J= 7Hz): 1.62 (t of t, 2H, J=
7,7Hz): 1.32 (t of q, 2H, J= 7,7Hz): 0.84 (t, 3H,J=
Hz). . 16 23 3 Found: 307.1460.
PART C: Preparation of 2-Butyl-1-14-(2-carboxybenz-amido)benzyl]-4-chloro-5-(methoxymethyl)-imidazole The above compound was prepared from 1-(4-aminobenzyl)-2-n-butyl-4-chloro-5-(methoxymethyl) imidazole (3.00 g, 9.7 mmol, 1 eq) and phthalic anhydride (1.44 g, 9.7 mmol, 1 eq) using the procedure of Example 2, Part D. Work-up yielded 1.71 g of an off-white powder, which was washed with acetonitrile.
-log 1 33409~
The insoluble material was filtered and dried to yield 1.17 9 of a white powder: m.p. 165.5-166.5C. NMR
(ZOO MHz, DMSO-d6) ~ 13.01 (m, lH): 10.39 (6, lH):
7.87 (d, lH, J= 7Hz): 7.75-7.46 (m, 5H): 7.03 (d, 2H, J= 8H7); ~.16 (s, 2H); 4.30 tS. 2H); 3.20 (8, 3H):
2.54 (t, 2H, J= 7Hz); 1.54 (t of t, 2H, J= 7,7Hz);
1.30 (t of q, 2H, J= 7,7Hz): 0.83 (t, 3H, J= 7Hz).
Anal. Calcd. for C24H26ClN304:C, 63.22: H, 5.75: Cl, 7.78. Found: C, 63.54; H, 5.76; Cl, 7.58.
Examples 5-18 6hown in Table 1 were prepared or could be prepared by t~e procedures described in Examples 2-4 from the appropriately sub6tituted aniline derivative and a suitable anhydride or acid c~loride. Other solvents, such as benzene or et~yl acetate may be substituted for chloroform.
Table 1 1 3 3 4 0 9 . 5 o ~ ` NHCR
Ex. 6 No. R R R7 R8 ~ n-butyl Cl CH2 0 ~CH3 (oil)a o ~ -HO ~ n-butyl Cl CH2CO2CH3 138.0-141.0 N,O2 ~
HO ~ ~ n-butyl Cl CH2CO2CH3 184.0-186.0 ~ F
3 8 HO ~ ~ F n-butyl Cl CH2CO2CH3 169.0-170.5 HO ~ n-butyl Cl CH2CO2CH3 172.0-173.5 ~: , Table 1 (cont'd ) 1 3340~
No. _ R _ R8 MP(C~
10 ~ n-butyl Cl CH2OCCH3 140.0-144.5 O
lS , 2 2 3 2 Preferred for their antihyperten6ive activity arenovel compound6 having the formula:
~ 2 (II) 13 1 3340~
Wherein ~13 Rl is -CO2H; -NHSO2CF3; ~ \N ;
and ~ al3 R6 is alkyl of 3 to 10 carbon atoms, alkenyl of 3 to 10 carbon atoms, alkynyl of 3 to 10 carbon atoms, cycloalkyl of 3 to 8 carbon atoms, benzyl substituted on the phenyl ring with up to two groups selected from alkoxy of 1 to 4 carbon atoms, halogen, alkyl of 1 to 4 carbon atoms, and nitro:
R8 is phenylalkenyl w~erein the aliphatic portion is 2 to 4 carbon atoms, -(CH2)m-imidaZl--(CH2)m-1,2,3-triazolyl optionally sub6ti-tuted with one or two groups selected from C02CH3 or alkyl of 1 to 4 carbon atoms, o (CH2)m-tetrazolyl, -(CH2)nORl ; -(CH2)nocRl4:
-CH=CH(CH2)~CR16, -CH=CH(CH2)6CHOR
O O
-(cH2)ncR ; _(cH2)nNHcoR ; ~(CH2)nNHS2Rl ;
O
-(CH2)mF; -CR16;
R13 is -CO2H, -CO2R , NHSO2CF3; and ~ ~ ;
N' 14 1 3340~
R is H, alkyl of 1 to 5 carbon atoms, OR , or NR R
X is carbon-carbon single bond, -CO-, -CON- , 2 H2 ~ -,N2CO3-, -OCH2-, -CH2O-, -SCH2-, -CH2S-, -NHCH2-, -CH2NH- or -CH=CH-: and pharmaceutically acceptable salts of these compounds.
More preferred are compounds of the preferred scope where:
R is H, alkyl of 1 to 4 carbon atoms, halogen, or alkoxy of 1 to 4 carbon atoms:
R6 is alkyl, alkenyl or alkynyl of 3 to 7 carbon atoms;
R7 is H, Cl, Br, or CF3;
R is -(CH2)mOR ; -(CH2)mOCR : -CH=CH-CHOR 5:
O O
-(CH2)mCR16: -CH2NHCOR10;
-(CH2)mNHSO2R ; CH ~ ~N ; or -COR
H
R10 is CF3, alkyl of 1 to 6 carbon atoms or phenyl;
R is H, or alkyl of 1 to 4 carbon atoms;
R13 is CO2H; C02CH2OCOC(CH3)3; NHS02CF3 and ~\ -t ' H
1 3~4092 R i~ H, or alkyl of 1 to 4 carbon atoms;
R is H, alkyl of 1 to 4 carbon atoms, or acyl of 1 to 4 carbon atoms;
R is H, alkyl of 1 to 5 carbon atoms; opl : or r__~
O
m i~ 1 to 5;
X = ~ingle bond, -0-; -C0-; -NHC0-; or -OCH2-; and pharmaceutically acceptable salt~.
Specifically preferred for their antihypertensive activity are:
2-Butyl-4-chloro-1-t~2'-(lH-tetrazol-.5-yl)biphen-yl-4-yl)methyl~-5-(hydroxymethyl)imidazole.
Z-Butyl-4-chloro-1-t(2'-carboxybiphenyl-4-yl)-methyl]-5-(hydroxymethyl)imidazole.
2-Butyl-4-chloro-1-~(2'-carboxybiphenyl-4-yl)-methyl]-5-[(methoxycarbonyl)aminomethyl]imidazole.
2-Butyl-4-chloro-l-t(2l-carboxybiphenyl-4-yl)-methyl]-5-[(propoxycarbonyl)aminomethyl]imidazole.
2-Butyl-4-chloro-1-[(2'-carboxybiphenyl-4-yl) methyl]imidazole-5-carboxaldehyde 2-Butyl-1-[(2'-carboxybiphenyl-4-yl)methyl]-imidazole-5-carboxaldehyde 2-(lE-Butenyl)-4-chloro-1-[(2'-carboxybiphenyl-g-yl)methyl]-5-(hydroxymethyl)imidazole 2-(lE-Butenyl)-4-chloro-1-[(2'-carboxybiphenyl-4-yl)methyl]imidazole-5-carboxaldehyde 2-Propyl-4-chloro-1-[2'-(lH-tetrazol-5-yl)biphenyl-4-yl)methyl~-5-(hydroxymethyl)imidazole 2-Propyl-4-chloro-1-t2'-(lH-tetrazol-5-yl)biphenyl-4-yl)methyl~imidazole-5-carboxaldehyde 2-Butyl-4-chloro-1-t2'-(lH-tetrazol-5-yl)biphenyl-4-yl)methyl~imidazole-5-carboxaldehyde 16 1 3~40q 2 2-(lE-Butenyl)-4-chloro-1-~2'-(lH-tetrazol-5-yl)biphenyl-4-yl)methyl]-5-hydroxymethyl)imidazole 2-(lE-Butenyl)-4-chloro-1-[2'-(lH-tetrazol-5-yl)biphenyl-4-yl)methyl]imidazole-5-carboxaldehyde and pharmaceutically acceptable 6alts thereof.
Note that throughout the text when an alkyl substituent is mentioned, the normal alkyl structure i6 meant (i.e., butyl is n-butyl) unless otherwi6e 6pecified.
Al60 within the 6cope of thi6 invention are pharmaceutical compositions compri6ing a 6uitable pharmaceutical carrier and a compound of Formula (1), and methods of usinq the compounds of Formula (I) to treat hypertension and conge6tive heart failure. The compounds of this invention can also be used a6 diagnostic agents to test the renin angiotensin 6ystem.
It 6hould be noted in the foregoing 6tructural formula, when a radical can be a 6ubstituent in more than one previously defined radical, that fir6t radical can be selected independently in each pre-viously defined radical. For example, Rl, R2 and R3 can each be CONHOR12. R12 need not be the 6ame 6ubstituent in each of Rl, R2 and R3 but can be selected independently for each of them.
Synthesis The novel compounds of Formula (I) may be prepared using the reaction6 and technique6 described in this section. The reactions are performed in a 601Yent appropriate to t~e reagentc and material~
employed and suitable for the transformation being effected. It is understood by those skilled in the art of organic synthesis that the functionality present on the imidazole and other portions of the 17 1 3340~
molecule must be consistent with the chemical transformations proposed. This will frequently necessitate judgment as to the order of synthetic steps, protecting groups required, deprotection conditions, and activation of a benzylic position to enable attachment to Ditrogen on the imidazole nucleus. Throughout the following 6ection, not all compounds of formula (~) falling into a given class may necessarily be prepared by all method~ described for that class. Substituents on the starting materials may be incompatible with 60me of the reaction conditions reguired in some of the methods described. Such restrictions to the 6ubstituents which are compatible with the reaction conditions will be readily apparent to one skilled in the art and alternative methods described must then be used.
Scheme1 1 334092 R3--~Ni 2) ,~CH2X R
/X = Br, Cl, OTs, OMs NHr NH3 ~ R1- 4-NO2 NH2 7 or o R7 or R8 R~ +R6~ N ~ R7 or R8 ~ R H
R~l 4 5 6 ~2~\R3 NH o R6~NH (HO)C~ R8 N~ RR7 b) , n~ , ~
N--, R8 \¢3 CN R N 1 ~--R7 H base ~
N ,~ RR7 ~/ CN CO2H
~H
11 N~N
N - N~
Generally, compounds of Formula (3) can be prepared by direct alkylation onto imidazole (1) prepared as described in U.S. 4,355,040 and references cited therein, with an appropriately protected benzyl halide, tosylate or mesylate (2) in the pre~ence of base, as shown in path a). Preferably, the metallic imidazolide salt is prepared by reacting imidazole (1) with a proton acceptor such a~- MH where M i6 lithium, sodium or potassium in a solvent such as dimethylformamide (DMF) or by reacting it with a metal alkoxide of formula MOR where R is methyl, ethyl, t-butyl or the like in an alcohol solvent such a8 ethanol or t-butanol, or a dipolar aprotic solvent such as dimethylformamide. The imidazole ~alt i6 dissolved in an inert aprotic solvent such a~ DMF, and treated with an appropriate alkylating agent (2).
Alternatively, imidazole (1) can be alkylated with a benzyl halide (2, where X=Br, Cl) in the presence of a base such as sodium carbonate, potassium carbonate, triethylamine or pyridine. The reaction is run in an inert solvent such as DMF or DMSO at 20C to the reflux temperature of the solvent for 1-10 hour~.
For example, the 4-nitrobenzyl intermediate (3a, wherein Rl = 4-N02, R2 ~ R3 = H) may be obtained by direct alkylation onto imidazole (1) with a 4-nitrobenzyl halide, tosylate or mesylate in the presence of base.
If R and R are different, mixtures of two regioisomer alkylation products (3b, and 3c) are obtained in which R7 and R8 are interchanged.
When R is CHO the alkylaSion is 8uch that the benzyl group becomes attached to the adjacent nitrogen preferentially. These isomers possess distinct physical and biological properties and can usually be separated and isolated by conventional separation techniques such as chromatography and~or crystallization.
-1 33409~
1~ p8 R6~ R9 RI~R
1~ ~
~ 3c 3d; R6 = n-Bu, R7 - Cl3e; R6 , n-Bu, 10R = CH2C02Me, R7 = Cl R8 ~ CH20H
R = 4-NHC ~3 Rl ~ 4~H
15CF3S02N I~J
R2 , R3 . H
R = R = H
In all 6erie6 examined, the more rapidly eluted i60mer of a given pair has greater biological potency than the le66 rapidly eluted i60mer. The absolute 6tructure of the compound6 3d and 3e has been confirmed by X-ray cry6tallographic analy6i6 to e6tabli6h the relation6hip between structure, phy6ical propertie6 and biological activity. Sulfonamide 3d i6 the more rapidly eluted i60mer in it6 serie6, acid 3e i6 the le6s rapidly eluted i60mer in it6 6erie6.
Alternatively, any properly functionalized benzylamine derivative (4) may be converted to imine (6) by treatment with an acylamino ketone (5) in the pre6ence of an inert 601vent such a6 benzene, toluene, or the like, and a catalytic amount of p-toluene-6ulfonic acid or molecular sieve6, N. Engel, and W. Steglich, Liebiq6 Ann. Chem., 1916, (197B), or in the pre6ence of alumina, F. Texier-Boulet, SYnthe6i 679 (19~5). The re6ulting imine (6) can be cyclized 21 1 3340q2 to the N-benzyl imidazole (3) with phosphorus penta-chloride (PC15), phosphorus oxychloride (POC13) or triphenylphosphine (PPh3) in dichloroethane in the pre6ence of a base 6uch a6 triethylamine, N. Engel and W. Steglich, Liebiq6 Ann. Chem., 1916, (1978).
Acylamino ketone (5) i6 readily obtainable from amino acid6 via the Dakin-We6t reaction, H.D. Dakin, R. We6t, J. Biol. Chem., 78, 95 and 745 (1928), and various modification6 thereof, W. Steglich, G. Hofle, Anqew. Chem. Int. Ed. Enql., 8, 981 (1969); G. Hofle, W. Steglich, H. Vorbr~ggen, Anqew. Chem. Int. Ed.
Enql., 17, 569 (1978); W. Steglich, G. Hofle, Ber., 102, 883 (1969), or by selective reduction of acyl cyanides, A. Pfaltz, S. Anwar, Tet. Lett. 2977 (1984), or from a-halo, a-to6yl or a-mesyl ketone6 via the appropriate 6ubstitution reactions that one skilled in the art will readily recognize.
The functionalized benzylamine6 (4) may be made from the corre6ponding benzyl halide, tosylate or mesylate (2) via di6placement with a nitrogen nucleo-phile, a procedure familiar to one skilled in the art. Thi6 di6placement may be achieved using azide ion, ammonia, or phthalimide anion, etc., in a neutral 601vent such as dimethylformamide, dimethyl6ulfoxide etc., or under phase transfer condition6. The benzyl halide (2) may be made by a variety of benzylic halo-genation methods familiar to one 6killed in the art, for example benzylic bromination of toluene derivative6 with N-bromo6uccinimide in an inert solvent 6uch a6 carbon tetrachloride in the pre6ence of a radical initiator 6uch a6 benzoyl peroxide at temperature6 up to reflux conditions.
A wide variety of toluene derivatives may be made rom simple electrophilic 6ubstitution reactions on an aromatic ring. Thi6 includes nitration, 6ulfonation, -22 1 33409~
phosphorylation, Friedel-Craft6 alkylation, Friedel-Crafts acylation, halogenation, and other similar reactions known to one skilled in the art, G. A. Olah, "Friedel-Crafts and Related Reaction6," Vol. 1-5, s Inter~cience, New York, (1965).
Another way to 6ynthe6ize functionalized benzyl halide6 is via chloromethylation of the corresponding aromatic precur60r. Thu6, the appropriately 6ub6ti-tuted benzene ring may be chloromethylated with formaldehyde and hydrochloric acid (HCl) for example with or without an inert solvent such a6 chloroform, carbon tetrachloride, light petroleum ether or acetic acid. A Lewi6 acid such as zinc chloride (ZnC12) or a mineral acid 6uch a6'pho6phoric acid may al60 be added a6 a cataly6t or conden6ing agent, R. C. Fu60n, C. H. McKeever, Orq. Reactions, 1, 63 (1942).
Alternatively, N-benzylimidazole6 (3) can al60 be prepared a6 shown in path b) by orming an R 6ub-6tituted amidine (7) from an appropriately ~ub6tituted benzylamine (4) which i6 in turn reacted with an a-haloketone, a-hydroxyketone (8), a-haloaldehyde, or a-hydroxyaldehyde, F. Kunckell, Ber., 34, 637 ( 1901 ) .
As 6hown in path a), imidazole (1) may be alkylated by a variety of benzyl derivative6. The6e include compounds with latent acid functionalitie6 6uch as o, m, and p-cyanobenzylhalide6, me6ylate6 or to6ylate6 as 6hown in path c). Nitrile6 of formula (9) may be hydrolyzed to carboxylic acid6 of formula (10) by treatment with strong acid or alkali. Prefer-ably, treatment with a 1:1 (v/v) mixture of concen-trated aqueous hydrochloric acid/glacial acetic acid at reflux temperatures for 2-96 hours or by treatment with lN sodium hydroxide in an alcohol solvent 6uch as ethanol or ethylene glycol for 2-96 hours at tempera-23 1 3340~2 tures from 20C to reflux can be used. If anothernitrile group is present it will al~o be hydrolyzed.
The nitrile functionality can also be hydrolyzed in two steps by first stirring in sulfuric acid to form the amide followed by hydrolysi6 with sodium hydroxide or a mineral acid to give the carboxylic acid (10).
The nitriles (9) can be converted into the corresponding tetrazole derivative (11) by a variety of methods using hydrazoic acid. For example, the nitrile can be heated with ~odium azide and ammonium chloride in DM~ at temperatures between 30C and reflux for 1-10 day~, J. P. Hurwitz and A. J. Tomson, J. Orq. Chem., 26, 3392 (1961). Preferably, the tetrazole is prepared by the l,3-dipolar cycloaddition Of trialkyltin or triaryltin azides to the appropriately substituted nitrile as described in detail by Scheme 15.
The starting imidazole compounds (1) are readily available by any of a number of standard methods. For example, acylaminoketone (5) can be cyclized with ammonia or equivalents thereof, D. Davidson, et al., J. Orq. Chem., 2, 319 (1937) to the corresponding imidazole as ~hown in Scheme 1. The corresponding oxazole can also be converted to imidazole (1) by action of ammonia or amines in general, H. Bredereck, et al., Ber., 88, 1351 (1955); J. W. Cornforth and R. H. Cornforth, J. Chem Soc., 96, (1947).
Several alternative routes to imidazoles (1) are illustrated in Scheme 2. As shown in Scheme 2 equa-tion a), reaction of the appropriate R6 substitutedimidate esters (12) with an appropriately substituted a-hydroxy- or a-haloketone or aldehyde (8) in ammonia leads to imidazoles of formula (1), P. Dziuron, and W. Schunack, Archiv. Pharmaz., 307 and 470 (1974).
-24 1 3340~2 The 6tarting imidazole compounds (1) wherein R and R are both hydrogen can be prepared as shown in equation b) by reaction of the appropriate R6-substituted imidate ester (12) with a-aminoacetaldehyde dimethyl acetal (13), ~. R.
Grimmett, Adv. ~eterocyclic Chem., 12, 103 (1970).
As 6hown in equation c), imidazole (15: wherein R = hydrogen and R = CH20H) can be prepared by treatment of the imidate ester (12) witb 1,3-dihydroxyacetone (14) in ammonia by the procedure described in Archive der Pharmazie, 307, 470 (1974).
Halogenation of imidazole (15) or any imidazole wherein R or R8 is hydrogen is preferably accom-pli6hed by reaction with one to two equivalent6 of N-halosuccinimide in a polar solvent such as dioxane or 2-methoxyethanol at a temperature of 40-100C for 1-10 hours. Reaction of the halogenated imidazole (16) with a benzylhalide (2) in the manner described in Scheme 1 affords the corresponding N-benzylimidazole (17); wherein R7 is halogen and R8 is CH20H). This procedure i6 described in U.S. Patent 4,355,040.
Alternatively, imidazole (17) can be prepared by the procedure described in U.S. Patent 4,207,324.
Compounds of formula (17) can also be prepared by treatment of the starting imidazole compound (1) wherein R7 and R8 are both hydrogen, with the appro-priate benzyl halide followed by functionalization of R7 and R8 by treatment with formaldehyde as de6cribed in E. F. Godefroi, et al., Recueil, 91, 1383 (1972) followed by halogenation as was described above.
As shown in equation d) the imidazoles (1) can also be prepared by reaction of R6 sub6tituted amidines (18) with an a-hydroxy- or a-haloketone or aldehyde (8) as described by F. ~unckel, Ber., 34, 637, (1901).
1 3340q 2 As shown in equation e), preparation of the nitroimidazoles (1, R or R = N02) is preferably accomplished by heatin~ the appropriate starting imidazole in a 3:1 mixture of conc. sulfuric acid/conc. nitric acid at 60-100C for 1-6 hours.
Nitration of t~e imidazole (15) can be achieved by first converting the hydroxymethylimidazole to tbe corresponding chloromethylimidazole (22) employing thionyl chloride or oxalyl chloride. Nitration, as described above, followed by hydrolysis provides the nitroimidazoles (24).
Imidazoles (21) where R7 and R8 = CN can be prepared as ~hown in equation f) by reaction of R6 substituted ortho e~ters, ortho acids or aldehydes (followed by oxidation of the aldehyde) with diamino-maleonitrile (20) by the procedure described by R. W.
Begland et al., J. Orq. Chem., 39, 2341 (1974). Like-wise, R6 substituted imidate esters (12) also react with diaminomaleonitrile to give 4,5 dicyanoimidazoles (21). The nitrile groups can be further elaborated into other functional groups by methods familiar to one skilled in the art.
a) NH-HCI l 334092 R6 OCH2CH3 (Cl)HO~ R8 NH3 b) 12 + H2NCH2CH(OMe)2 ~R6 ~ ;~
(wherein R7=R3=H) c) 12 + CCH2oOH ~ R61 N~OH
/ halogenation X ~ X
N~,OH , R61 H X=Br,CI H
16 ~\J--R3 NH
R6J~ NH2 + (Cl)HO~ R3 X,' _ 27 1 3~40q2 S .~ .
R6J~;~3 cl HNO3/H2SO4 ~CI
NO
N
NH
CN
H2N CN N ~
f) R3--C(OMe)3 + ~( R6--~N~--CN
19 or 12 R7 Rs = CN
~, ~' Scheme3 7 1 3 3 4 0 9 2 a) 61 ~CH20H ,Q 'RCH2CI ~N ~RCH2CN
R1~\R2R3 R~\R2R3 R1~ J2R3 17(where R7=CI) 2 N--R7 R6~N~--CO2CH3 or NaOH l ~ I
1~R2 R1~ R2R3 N ~:H2oCR14 b) 17(R C )2~
or Tl --R3 R14COCI 1/~ R2 R
6~ H20R11 c) 17 ~ N ~ ?5 \~ ~\J2 N ~CF3 N ~.l 8 _~ ' R8 R N CF3Cu d) ~ - R3 R,~R2R3 ,,~;,~
29 1 33409~
A6 6hown in Scheme 3, path a) for benzylimid-azole6 (17) where R = Cl and R = CH20H, the hydroxy-methyl g~oup6 may be ea6ily converted to the corre-6ponding halide, me6ylate or to6ylate by a variety o$ method6 familiar to one 6killed in the art.
Preferably, the alcohol (17) is converted to the chloride (25) with thionyl chloride in an inert 601vent at temperature~ of 20C to the reflux temperature of the 601vent.
Chloride (25) may be di6placed by a variety of nucleophile6 by nucleophilic di6placement reaction procedure6 familiar to one 6killed in the art. For example, exce6s 60dium cyanide in DMS0 may be u6ed to form cyanomethyl derivative6 (26) at temperature6 of 20C to 100C.
Nitrile (26) may be hydrolyzed to acetic acid derivative (27), by a variety of method6. The6e method6 include method6 de6cribed previou61y for the hydroly6i6 of nitrile6 of formula (9). Example6 of de6ired acid6 and ba6e6 for thi6 hydroly6i6 include mineral acid6 6uch a6 6ulfuric acid, hydrochloric acid, and mixture6 of either of the above with 30-50%
acetic acid (when 601ubility i6 a problem), and alkali metal hydroxide6 6uch a6 60dium hydroxide or pota66ium hydroxide. The hydroly6i6 reaction proceed6 under heating at temperature6 ranging from 50-160C for 2-48 hour6. Carboxylic acid (27) may be e6terified by a variety of method6 without affecting other part6 of the molecule.- Preferably, (27) i6 refluxed in a hydrochloric acid/methanol 601ution for 2-48 hour6 to qive e6ter (2~).
E6ter (28) may be hydrolyzed to carboxylic acid (27), for in6tance, after R , R and R3 have been elaborated. Variou6 method6, acidic or ba6ic, may be u6ed. For example, compound (28) i6 6tirred with 0.5N
-potassium hydroxide in methanol, or if base ~oluble, it is stirred in l.ON sodium hydroxide for 1-48 h at 20C to reflux temperatures.
Hydroxymethyl derivative (17) may be acylated to give (29) by a variety of procedures. As shown in path b) acylation can be achieved with 1-3 equivalents of an acyl halide or an anhydride in a 601vent ~uch as diethyl ether, tetrahydrofuran, methylene chloride or the like in the presence of a base such as pyridine or triethylamine. Alternatively (17) may be acylated by reaction witb a carboxylic acid and dicyclohexylcarbo-diimide (DCC) in the presence of a catalytic amount of 4-(N,N-dimethylamino)pyridine (DMAP) via the procedure described by A. Hassner, Tet. Lett., 46, 4475 (1978).
Treatment of (17) with a solution of carboxylic acid anhydride in pyridine optionally with a catalytic amount of DMAP at temperatures of 20-100C for 2-48 hours is the preferred method.
The ether (30) can be prepared from the alcohol (17) as shown in path c) by methods such as treatment of (17) in a solvent such as dimethylformamide or dimethylsulfoxide with potassium t-butoxide, sodium hydride, or the like followed by treatment with RllL
at 25C for 1-20 hours, where L is a halogen, tosylate or mesylate.
Alternatively, treatment of (17) with l-S
equivalents of thionyl chloride in chloroform for 2-6 hours at 25C followed by treatment of the intermediate (25) with 1-3 equivalents of MOR 1, where M is 60dium or potassium, for 2-10 hours at 25C either in RllOH
as solvent or in a polar solvent 6uch as dimethylform-amide or the like will also yield ether (30).
The ether (30) can also be prepared for example by hea~ting (17) for 3-lS hours at 60-160C in R OH
containing an inorganic acid such as a hydrochloric acid or sulfuric acid.
-31 1 3340~
Compound (17) can be dehalogenated to compound (31) preferably by catalytic hydrogenoly6i6 (over an appropriate cataly6t 6uch a6 lOS palladium on carbon) in methanol at 25C for 1-6 hour6 or by treatment with zinc metal in acetic acid.
A6 6hown in Scheme 3, the trifluoromethyl imidazole6 (33) can be prepared from the corresponding iodoimidazole6 (32) by treatment with trifluoromethyl copper, J. Am. Chem. Soc., 108, 832 (1986).
N-arylimidazole6 of formula I (compound6 wherein r=o) can be prepared by the following method6, it being under6tood by one 6killed in the art that certain manipulations, protecting and deprotecting step6, and other 6ynthetic procedure6 di6clo6ed above may be nece66ary to produce compounds with the de6ired combination6 of R , R , R and R13-A6 shown in Scheme 4, equation a) the reactionof aniline derivative (34) with imidate e6ter (12) to form the sub6tituted amidine (35) provide6 material which can be cyclized with dihydroxyacetone to form 6tructure (36). Subsequent elaboration into (I) provides the N-arylimidazole compound6 of the invention.
Alternatively as 6hown by equation b) the Marckwald procedure, de6cribed by Marckwald et al., Ber., 22, 568, 1353 (1889): Ber., 25, 2354 (1892) can be u6ed to form a 2-mercaptoimidazole (38) from aniline derivative (34) via isothiocyanate (37).
De6ulfurization of (38) with dilute nitric acid followed by anion formation at the 2-position of the imidazole (39) and reaction with R6X where X is Cl, Br, I, allow6 the formation of (40) which can be 6ub6equently elaborated to I.
A variation of ~arckwald'6 proces~ a6 6hown in equation c) using an a-aminoketone (41) and isothiocyanate (37) can al60 be employed, 6ee Norri6 and McKee, J. Amer. Chem. Soc., 77, 1056 tl955) can also be employed. Intermediate (42) can be converted to (1~ by known 6equence6. The general procedure of Carboni et al., J. Amer. Chem. Soc., 89, 2626 (1967) (illustcated by equation d)) can al60 be u6ed to prepare N-aryl substituted imidazole6 from appropriate haloaromatic compounds (43; X=F, Cl, Br) and imidazole6 (1):
Scheme 4 ~H
2 o~t ~ R13 ~ R13 Co(cH2oH) \~
R6'~ R6 ~ <
~ 3 ~H ~ Rl3 Scheme 4 (continued) HS ~~;;3 b) ¢1 ~ 1) H2NCH2CH(OEt)2 ~1 ~3_ R13 ~3_ R13 3_ R13 HNO3, R6~ 3 N;~
(1) nBuLi ~3_ R13 ~_ R13 HS ~~
c) R8COCH2NH2 + 37 ~ I
3_ R13 42 N ~ R3 X R6--~N~ 7 N~ R8 ~ Na2CO3 hR
H R + ~_ DMF ~_ R13 ~ I
~ 1 3340~2 In various synthetic routes Rl~ R2 and R3 do not necessarily remain the same from the starting compound to the final products, but are often manipulated through known reactions in the intermediate steps as shown in Schemes 5-~2. All of the transformations shown in Sch~mes 5-10 and 12 can also be carried out on the terminal aromatic ring (i.e., biphenyl ring).
Scheme 5 R6 ~ N~ R IN ~0] R N, (CH2)r (CH2)r (CH2)r R ~ R2R ~-SH R 3~J
44 ~ 46 As shown in Scheme 5, compounds where R1 is a sulfonic acid group may be prepared by oxidation of the corresponding thiol (45). Thus, an N-benzylimidazole derivative bearing a thiol group may be converted into a sulfonic acid (46) by the action of hydrogen peroxide, peroxyacids such as metachloroperoxybenzoic acid, potassium permanganate or by a variety of other oxidizing agents, E.
E. Reid, Org~n;c Chem1stry of Biv~lent Sulfur, 1, Chemical Publishing Co., New York, 120-121 (1958).
~ 35 I 3~4092 Aromatic hydroxy or thiol group6 are obtained from deprotection of the corre6ponding alkyl ether or thioether6. Thu6, for example, a methyl ether or a methyl thioether derivative (44) of an N-benzylimid-azole containing one or more aromatic rings may beconverted into the free phenol or thiophenol (45) by the action of boron tribromide ~ethyl ~ulfide, P. G.
Willard and C. F. Fryhle, Tet. Lett., 21, 3731 (1980):
trimethylsilyl iodide, ~. E. Jung and M. A. Ly6ter, J. Orq. Chem., ~2, 3761 (1977); RSEt and derivative6 thereof, G. I. Feutrill, R. N. ~irrington, Tet. Lett., 1327, (1970), and a variety of other reagent6.
Alternatively, N-benzylimida201es may be sulfonated by 6tirring vith H2S04 at a variety of different concentrations or with other sulfonating agent6 6uch a6 chlorosulfonic acid or sulfur trioxide with or without complexing agents ~uch a6 dioxane or pyridine at temperature6 from O to 200C with or with-out 601vent, K. LeRoi Nel60n in Friedel-Craft6 and Related Reaction6, III part 2, G. A. Olah, ed., Inter6cience Publ., 1355 (1964).
The 6ynthe6i6 of compound6 where Rl i6 a 6ulfate, pho6phate or pho6phonic acid are depicted in Scheme 6:
Scheme 6 N~ R3 R N
(cH2)r (CH2)r ~J R2~--o~ - OH
47 ~CI5 48 \\~ ~ R7 (CH2)r R2~J OP- OH
b) 61 ~ - R7 R6 ~N~ 1 ~ R7 (CH2)r AIC13 (cH2)r (CIH2)r R2~ PC12 ~--PC4 ~;where R1 = H 50 51 N~R
~; R7 PSCI3 H2 (CH2)r AICI3 ~5~ 0 R2~`/~ IP--OH
Scheme 6 (continued) 1 334~q2 R N . ~ N ~ R87 (CH2)r Cu(l) (CH2)r ~--N2+X- 2~J PCI3X-54 X = BF4, SiF6, ZnCI3 N~,R37 R N + 3HCI
(cH2)r 2~--P--OH
N--R37 ~ ; R7 (CH2)r + (EtO)3P ~ (CH2)r ~ 52 R2~3/B(cl) 3~ OEt 5~ R2, R3, R4 ~ halogen (EtO)3P
NiX2 (X = Halogen) -38 1 3340~2 N-Benzylimidazoles containing a phenolic hydroxyl group 147) may be readily converted into the corresponding sulfate (48) or phosphate (49). As shown in equation a), reaction of the phenol with a sulfur trioxide-amine complex will give the corre-sponding sulfate (48), E. E. Gilbert, Sulfonation and Related Reactions, Interscience, New York, chapter 6 (1965). Reaction of the phenol (97) with phosphorus pentachloride followed by hydrolysis will give the corresponding phosphate (49), G. M. ~osolapoff, Organophosphorus Compounds, John Wiley, New Yor~, 235 (1950).
As shown in equation b) N-benzylimidazoles may be converted into the corresponding phosphonic acids by reaction with phosphorus trichloride (PC13) and aluminum chloride (AlC13) in an inert sol~ent for 0.5-96 hours from temperatures of 25C to the reflux temperatures of the solvent. Appropriate workup followed by reaction with chlorine (C12) and subsequent hydrolysis of the tetrachloride (51) gives the phosphonic acid derivative (52), G. M. Kosolapoff in Orq. Reactions, 6, R. Adams, editor, John Wiley and Sons, New York, 297 (1951). Another more direct route involves reaction of the N-benzylimidazole with PSC13 and AlC13 followed by hydrolysis, R. S.
Edmunson in Comprehensive Orqanic Chemistry, Vol. 2, D. Barton and W. D. Ollis editors, Pergamon Press, New York, 1285 (1979).
Alternatively, equation c) illustrates that aryl phosphonic acids (52) may be formed from reaction of the corresponding diazonium salt (53) with PC13 in the presence of Cu(I) followed by hydrolysis with water (ibid, p. 1286).
As shown in equation d), the aryl halides (55) may be photolyzed in the presence of phosphite esters to give phosphonate esters (56), R. Kluger, J. L. W.
39 1 3340q2 Chan, J. Am. Chem. Soc., 95, 2362, (1973). These same aryl halides also react with phosphite ester6 in the presence of nickel or palladium salts to give pho6-phonate esters, P. Tav6, Chem. Ber., 103, 242B (1970), which can be subsequently converted to phosphonic acid6 (52) by procedures known to one skilled in the art.
N-Benzylimidazoles containing an aldehyde or ketone (57) may be reacted with a phosphorus trihalide followed by water hydroly6i6 to give a-hydroxypho6-phonic acid derivative6, G.M. ~0601apoff, op. cit., 304, as 6hown in Scheme 7.
Scheme 7 N ~,8 ; R6 2~ ~120 20(cH2)r (CH2)r R2R~ CR R ~ - r-H
S7 ~R ~ R, ~ lltyll58 ~J
-1 3340~2 Compounds where R is -CONHOR may be pre-pared as shown in Scheme 8, by the treatment of a carboxylic acid (10) with 1-4 equivalents of thionyl chloride for 1-10 hours. This reaction can be run without sol~ent or in a nonreactive solvent such as benzene or chloroform at temperatures of 25-65C. The intermediate acid chlor~de is then treated with 2-10 equivalents of the appropriate amine derivative, H2N-OR , for 2-18 hours at temperatures of 25-80C
in a polar aprotic solvent such as tetrahydrofuran or dimethylsulfoxide to give the hydroxamic acid (59).
Scheme 8 R6 N > R6 N
~C~2H ~3-WDR12 ~
,~
Alternatively, the carboxylic acid (10) can be converted to the hydroxamic acid (59) according to the procedure in J. Med. Chem., 28, 1158 (1985) by employing dicyclohexylcarbodiimide, l-hydroxybenzo-triazole, and H2NOR or according to the procedure described in SYnthesis~ 929 (1985) employing the Vilsmeier reagent and H2NOR
Scheme 9 ~ 3340q2 ~ R7 ~ R7 ~ ;;; R7 (CH2)r (CH2)r ~ (CH2)r R ~ ~ CN3 21~--N=C=O
N~ R 7 ~ ~ R7 R-OH ~ N
R= alkyl, i.e. (CIH2)r (CH2)r (CH3)3SiCH2CH2 ,~--NHCOR '~ NH2 Aniline intermediate6 (63) are di6clo6ed in U.S.
Patent No. 4,355,040 and may be obtained from the corresponding nitro compound precur60r by reduction.
A variety of reduction procedure6 may be u6ed 6ucb a6 iron~acetic acid, D. C. Ow~ley, J. J. Bloomfield, Synthesi6, 118, (1977), 6tannou6 chloride, ~. D.
Bellamy, Tet. Lett., 839, (1984) or careful hydro-genation over a metal cataly6t 6uch a6 palladium.
A6 6hown in Scheme 9, aniline intermediate6 of N-benzylimidazole6 may al60 be prepared from the corre-6ponding carboxylic acid (10) or acid chloride via a Curtius rearrangement of an intermediate acyl azide (60). More modern method6 include u6ing diphenyl-pho6phoryl azide as a ~ource of azide, T. Shioiri, K. Ninomiya, S. Yamada, J. Am. Chem. Soc., 94, 6203 (1972), and trapping the intermediate i60cyanate (61) produced by the Curtius rearrangement witb 2-trimethyl-6ilylethanol and cleaving the re6ultant carbamate (62) with fluoride to liberate the amine (63), T. L. Cap60n and C. D. Poulter, Tet. Lett., 25, 3515 (1984).
Cla66ical procedures familiar to one 6killed in the art may al60 be employed.
Compound6 where Rl i6 -502NH2 may be made a6 6hown in Scheme 10:
-Scheme 10 1 3~40~2 ~ R6 ~ ~ R
(CH2)r (CH2)r ~ 502C1 2 ~ so 6~ ~
Sulfonamide compoun~s (65) may be made by reacting an arylsulfonyl chloride (64) with ammonia, or it6 equivalent. Unsub6tituted aryl6ulfonamide6 are made by reaction with ammonia in aqueous 601ution or in an inert organic 601vent, F. H. Bergheim and W. Braker, J. Am. Chem. Soc., 66, 1459 (1944), or with dry powdered ammonium carbonate, E. H. Huntre66 and J. S. Autenrieth, J. Am. Chem. Soc., 63, 3446 (1941):
E. H. Huntre66 and F. H. Carten, J. Am. Chem. Soc., 62, 511 (1940).
The sulfonyl chloride precur60r may be prepared by chlorosulfonation with chloro6ulfonic acid on the aromatic ring directly, E. H. Huntre66 and F. H.
Carten, ibid.; E. E. Gilbert, oP. cit., 84, or by reacting the corre6ponding aromatic diazonium chloride 6alt (53) with 6ulfur dioxide in the pre~ence of a copper cataly6t, H. Meerwein, et al., J. Prakt. Chem., tii], 152, 251 (1939), or by reacting the aromatic 6ulfonic acid (46) with PC15 or POC13, C. M. Suter, The Organic Chemi6trY of Sulfur, John Wiley, 459 (1948).
Linked ester compounds of formula (I) where R
o is -CO2CH(R )OCR can be made by procedures well known in penicillin and cephalosporin chemistry.
The purpose is to provide materials which are more lipophilic and which will be useful orally by rapid transit from the qut into the bloodstream, and which will then cleave at a sufficiently rapid rate to provide therapeutically useful concentrations of the active carboxylic acid form. The following review articles and references cited therein discuss this concept and the chemistry involved in preparing such compounds V. J. Stella, et al., Druqs, 29, 455-473 (1985); H. Ferres, Drugs of Today. 19 (9), 499-538 (1983); A. A. Sirkula, Ann. Repts. Med. Chem., 10, 306-315 (1975).
Experimental procedures which are applicable to the preparation of chemically stable linked esters are illustrated by equations a-e of Scheme 11.
Scheme 11 (a) RCO2Na + (CH3)3CC02CH2Br ~RC02CH2OCOC(CH3)3 G. Francheschi et al., J. Antibiotics, ~6, (7), 938-941 (1983).
(b) RCO2 + (CH3)2NCON(CH3)2 + ClCHOCOC(CH3)3 RCO2CHOCOC(CH3)3 J. Budavin, U.S. Patent 4,440,942 R~24 (c) RC02H ` RC02CH-OCOCHCH2C02CH3 -B. Daehne et al., G.B. Patent 1,290,787 25 (d)RCO2H > RCo2CHCONR22R23 Ferres, Chem. Ind., 435-440 (1980) 3 (e) R-CO2H > RHC ~
~ ' ,. ..
~, 46 1 3340~2 Clayton et al., Antimicrob. Aqents ChemotheraPY, 5, (6), 670-671 (1974) ln equations a-e: R= R 4 ~
R2~3 Compounds of Formula I where Rl is -C(CF3)20H
may be prepared as 6hown in Scheme 12.
Scheme 12 1 33409~
~; R7 N~ R87 --SiMe3 R3 CF3 71 ~2 ,~"~
.
llexafluoroisopropanol compounds (72) may be prepared by treatment of arylsilane (71) with 1-5 equivalents of hexafluoroacetone in a solvent such as methylene chloride at temperatures ranging from about -50 to 25C for a period of 2-10 hours. The requisite arylsilane (71) can be prepared using methods known to one skilled in the art such as the procedures described iQ Chapter 10 of Butterworth's "Silicon in Organic Chemistry".
Scheme 13 1 334092 N-- R87 1 ' R7 N-- R87 ~NO2 ~ NH2 >X3 3a 63 73 R13 H]
R8 / reductive ~R8 1 ~ R7 amination ; R7 ~
N--Z ~ (R23 ~ H
'23 o 76 z= ,ll3 HOC
77 Z=
o 78 Z=
1 3340q2 As shown in Scheme 13, compound (73) in which X=
-NHCO and R13= -COOH may be easily prepared, for example, by reacting aniline precursor (63) with a phthalic anhydride derivative in an appropriate solvent such as benzene, chloroform, ethyl acetate, etc. Often the carboxylic acid product will precipi-tate from solution with the reactants remaining behind, M.L. Sherrill, F.L. Schaeffer, E.P. Shoyer, J. Am.
Chem. Soc., 50, 474 (1928).
When R =NHS02CH3, NHS02CF3 or tetrazolyl (or a variety of other carboxylic acid equivalents), compound (73) may be obtained by reacting aniline (63) with the requisite acid chloride by either a Schotten-Baumann procedure, or simply stirring in a solvent such as methylene chloride in the presence of a base such as sodium bicarbonate, pyridine, or triethylamine.
Likewise, aniline (63) may be coupled with an appropriate carboxylic acid via a variety of amide or peptide bond forming reactions such as DCC coupling, azide coupling, mixed anhydride Eynthesis, or any other coupling procedure familiar to one 6killed in the art.
Aniline derivatives (63) will undergo reductive animation with aldehydes and ketones to form secondary amines (74). Thus the aniline is first stirred with the carbonyl compound in the presence of a dehydration catalyst 6uch as molecular sieves or p-toluenesulfonic acid. Afterwards the resultant imine is reduced to the amine with a borohydride reducing agent 6uch as sodium cyanoborohydride or sodium boro~ydride.
Standard catalytic hydrogenation reagents such as hydrogen and palladium/carbon can also be employed.
-51 1 3340q~
Alternatively, aniline (63) may be monoalkylated by reaction with ethyl formate followed by reduction with, for example, lithium aluminum hydride to produce the N-methyl derivative (74). Aniline6 (74) may in turn be reacted with carboxylic acid anhydrides and acid chlorides or carboxylic acids by any of the coupling procedure6 described previously to yield (73) where X= -N(CH3)C0-.
Aniline (63) or (74) or other intermediate anilines where the amino group may be located on another aromatic ring for example, al60 react with other anhydrides to make amide-carboxylic acid derivatives of formula (75). Thus, for example, maleic anhydride, 2,3-naphthalenedicarboxylic acid anhydride, and diphenic anhydride are reacted in a similar fashion to phthalic anhydride with aniline (63) or (79) to yield carboxylic acids (76), (77), and (78), respectively.
Phthalimide derivatives of aniline (63) may be made by a variety of methods, preferably by 6tirring aniline (63) with phthalic anhydride in acetic acid at a temperature betweén 20C and reflux, G. Wanag, A. Veinbergs, Ber., 75, 1558 (1942), or by 6tirring (63) with phthaloyl chloride, a base 6uch as triethylamine, and an inert solvent.
Aniline (63) may be converted into its tri-fluoromethanesulfonamide derivative or its trifluoroacetamido derivative preferably by reacting it with triflic anhydride or trifluoroacetic anhydride and a base such as triethylamine in an inert solvent ~uch as methylene chloride at -78C followed by warming to room temperature.
Compounds of 6tructure (I) where X i6 a carbon-carbon linkage which are depicted a6 (80) can be made as shown in Scheme 14.
Scheme 1 4 1 3 3 4 0 9 ~
R ;;~ ~ R~ R6lN, ~Q
~/ogenation Y=Br, Cl Sch~me 14 (Cont'~ 334092 Cl H3 R13 85 I~LI
d) ~
COOH N o R / t-Bu, etc.
~OCH3 ~OCH3 [~ OH
Equation a) illustrates that the biphenyl compounds (80) can be prepared by alkylation of imidazole (1) with the appropriate halomethylbiphenyl compound (79) by the general procedure described in Scheme 1.
The requisite halomethylbiphenyl intermediates (79) are prepared by Ullman Coupling of I81) and (~2) as described in 'IOrganic Reactions", 2, 6 (1944) to provide intermediates (83), which are in turn halogenated.
Halogenation can be accomplished by refluxing (83) in an inert solvent such as carbon tetrachloride for 1-6 hours in the presence of a N-halosuccinimide and an initiator such as azobisisobutyronitrile (equation b).
As shown in equation c), derivatives of intermediate (83) in which R13 is at the 2' position (~) can also be prepared by the method described in 54 l 334092 J. Orq. Chem., 41, 1320 (1976), that i6 Diel6-Alder addition of a 1,3-butadiene to a styrene (84) followed by aromatization of intermediate (85).
Alternatively, the 6ub6tituted biphenyl precur60r~ (83; where R = COOH) and their e6ters (89) can be prepared a6 illu6trated in equation d), which involve6 oxazoline compound6 a6 key intermediate6, A. I. Meyer6 and E. D. Mihelich, J. Am.
Chem. Soc., 97, 7383 (1975).
The 6ub6tituted biphenyl tetrazole6 (83; where ~Y
R13 = ~ SM) can be prepared from the nitrile precur60r ~(R13.CN) by the method6 de6cribed in Scheme 1, equation c) and Scheme 15, equation c).
However, a preferred method for preparing tetrazole6 i6 de6cribed in Scheme 15, equation6 a) and b). Compound6 (90) may be prepared by the 1,3-dipolar cycloaddition of trialkyltin or triphenyltin azide6 to the appropriately 6ub6tituted nitrile (B3) a6 in equation a). Alkyl i6 defined a6 normal alkyl of 1-6 carbon atom6 and cyclohexyl. An example of thi6 technique i6 de6cribed by S. Kozima, et al., J. Orqanometallic Chemi6trY~ 337 (1971). The required trialkyl or triaryltin azide6 are made from the requi6ite commercial trialkyl or triaryl tin chloride and 60dium azide. The trialkyl or triaryltin group i6 removed via acidic or ba6ic hydroly6i6 and the tetrazole can be protected with the trityl group by, reaction with trityl chloride and triethylamine to give (91). Bromination a6 previou61y de6cribed herein with N-bromosuccinimide and dibenzoylperoxide afford6 compound (92). Alkylation of (1) with the appropriately 6ub6tituted benzyl halide u6ing condition6 previou61y de6cribed followed by deprotection of the trityl group via hydroly6i6 1 33409~
affords ( _; R13 = tetrazole). Other protecting groups 6uch a~ p-nitrobenzyl and l-ethoxyethyl can be used instead of the trityl group to protect the tetrazole moiety. These groups as well as the trityl group can be introduced and removed by procedures described in Greene, Protective GrouPs in Orqanic SYnthesis~ Wiley-Interscience, (1980).
Scheme 15 CH~
Sn(R)3N3 'Sn(R)3 83 (R13=CN) 90 R = alkyl of 1 to 6 carbon atoms, phenyl 1);~
2) (PH)3CCl, TE~
c~3 a~2Br 2 5 ei~ N C(Phenyl)3 ~ C(Phenyl)3 ~N N95, D90 ~N
~v Scheme 15 (continued) l 3 3 4 0 9 2 .: N~ R3 R N 1)~ NaOEt R N N=N
H 2) Depro~ection ~H
80, (R13=tetrazole) c) 10 NH"CI ~ N ~
~,CN D~F [~ H,N
1 33409~
Compounds of structure 93-95 where X ls an -O-, -S-, or -N- linkage can be prepared as shown ln Scheme 16 by alkylatlon of lmldazole (1) with the appropriate benzyl halide (96).
Scheme 16 CH2Br ~-X
N~8 ~ - R13 1 j~ R7 96 ~--X
~ I
93; X=O ~--R13 94; X=S
~; X- N R26 .... .. . .
;
Scheme 16 (continued) 1 3340q2 b) f Hal CH3 97-100 ~~ CO2H
97; X=O / 101-104 ~; X=S
99; X=NH
100; X=NR26(R26~H) CH3 ~ CH2Hal ~X ~ ~X
1~ CO2CH3 [~ CO2H
109; X=O
~; X=S
111; X=NH
112; X=NR26 (R26;tH) -sg 1 3340~2 The halomethyldiphenyl ether tlO9) employed as an alkylating agent in the pre6ent invention is prepared as shown in equation b). An Ullman ether condensation of the phenol (97) and a halobenzoic acid S as de6cribed in Russian Chc-ical Revle~s, 43, 679 (1974) provides the intermediate acid (101). ~he conver6ion of llOl) into (109) ~s accompli6hed by esterification wit~ diazomethane to afford (105) followed by haloqenation employing the procedure used in the preparation of (79). The diphenylsulfide (110) and the diphenylamine (111) can be prepared from the appropriate thiophenol (98) or aniline (99) by thi6 procedure.
The tertiary diphenylamine (112) can be prepared from the secondary aniline (100) by the above procedure. Alternatively (107) can be alkylated by one of the following procedures: 1) direct alkylation of (~3) with R26L where L is a leaving group such as a halogen or to6ylate employing phase-transfer conditions and ultrasound as described ~n Tetrahedron Letters, 24, 5907 (1983), 2) treatment of (107) with 1-1.5 equivalents of an appropriate aldehyde and 0.5-5.0 equivalents of sodium cyanoborohydride in a solvent such as methanol at 25C at a pH of 3-6 for 1-24 hours, or 3) reductive amination of (~) employing an appropriate carboxylic acid and sodium borohydride as described in J. Am. Chem. Soc., 96, 7812 (1974). ~he tertiary amine (108) is t~en halogenated by the procedure previously described to qive (112).
Scheme 17 l 3340 9 2 ~R7 --R13 ~0 base ~R13 114; R13=2-Co2CH3, X=halide 1 15; R13=2-Co2CH3, X=H
N _j~R8 113; R13=2-Co2CH3 ~0 [~CO2H
x Compound6 of 6tructure (73) where X i6 -C0- are prepared a6 6hown in Scheme 17 by alkylation of imidazole (1) with the requi6ite benzoylbenzyl halide6. For example, e6ter6 (113) where R13 i6 2-C02CH3 are prepared by alkylation of imidazole (1) with carbomethoxybenzoyl benzyl halide (114).
E6ter (113) may be hydrolyzed to the corre6ponding carboxylic acid (116) by a variety of method6 including hydroly6i6 with a ba6e 6uch as 60dium hydroxide or pota66ium hydroxide in an alcoholic aqueou6 solvent 6uch a6 methanol~H20 at a temperature from 20C to the reflux temperature of the 601vent.
Carboalkoxybenzoylbenzyl halide6 (114) are prepared by benzylic halogenation of the corre6pondinq toluoylbenzene precur60r by a variety of method6 previou61y de6cribed herein. For example, methyl 2-(4-methylbenzoyl)benzoate (115) can be refluxed for 2-48 hour6 with N-bromo6uccinimide, benzoyl peroxide and carbon tetrachloride to effect benzylic bromination.
Scheme 18 l 334092 R6 l N~ R6 l N~ R l=~ R7 ~N-OR28 ~50 ~fNNHR27 ~ R13 ~ ~ R13 117 Rl3 118 [H] ~ooRR29o R13_~ 3 R6 l N~ ~ [H]R6 l N~ N ~ g8 ~OH ~ oCRl7 ~3_ R13~ R13 ~, R13 121 N _~ 122 ,1~ R7 R6 N~
~oR14 , - ~
63 1 3340~2 A6 6hown in Scheme 18 the toluoyl ketone6 (73:
where X=CO) may be further transformed into a variety of ketone derivative6 including compound6 where ~ i6 NR25 R290 oR30 OCOR OR
.. \~ . .
-C- , -C- , -CH , and -C-Reaction of ketone (73a) with a hydroxylamine or an appropriately 6ubstituted hydrazine will give the - re~ui6ite oxime6 (117) and hydrazones (118). ~eaction with alcohol6 in the pre6ence of an acidic catalyst with removal of water will qive ketal6 lll9).
Reduction, with lithium aluminum hydride, a metal borohydride, zinc/acetic acid or catalytic hydrogenation will give the corresponaing alcohol (120) or fully reduced methylene compound ~121) The6e alcohol6 may be acylated by a variety of anhydride6 or acid halide6 in the pre6ence of a base with or without 601vent to give the corre6ponding e6ter6 (122). The alcohol6 (120) may be converted into their corre6ponding ether6 (123) by reaction of the metal alkoxide with an alkyl halide, me6ylate or to6ylate in the appropriate 601Yent or by treatment with a mineral acid in an alcoholic 601vent, or by reaction of the alcohol with diazomethane G. Hilgetag and A. Martini, ~Preparative Organic Chemi6try~, John Wiley, New York, 355-368 (1972).
Compound6 of formula (I) where ~ iB -OCH2-, -SCH2-, and -NHCH2- are prepared a6 shown in Scheme 19.
Scheme 19 1 33409~
R N ~ R --~N~;
~¢--OR ~--OH ~¢ ~
12~; R = CH2Ph 126 127 ~ R13 125; R = CH3 N-- R 7 ~ R7 R6~N~
--SCH2Ph ~¢--SH
~¢ ~ reduotiveamination ~--HN
I 3340~
As illust~ated in Scheme 19, equation a, hydrolysi6 of benzyl ether (124) or methyl ether (125) a~fords hydroxy compound (126~ which can be alkylated with the a~propriate benzyl halide to give (127). In the case of the methyl ether6 (125), the hydroly6i6 step can be efected by heating the ether at tempera-ture6 of 50-150C for 1-10 hour6 in 20-60% hydrobromic acid, or heating at 50-90C in acetonitrile with 1-5 equivalent6 of trimethyl6ilyl iodide for 10-50 hour6 Lollowed by treatment with water. Hydrolysi6 can also be carried out by treatment with 1-2 equivalent6 of boron tribromide in methylene chloride at 10-30C for 1-10 hour6 followed by treatment with water, or by treatment with an acid 6uch a6 aluminum chloride and 3-30 equivalent6 of a 6ulfur-containing compound 6uch as thiophenol, ethanedithiol, or dimethyl di6ulfide in methylene chloride at 0-30C for l-Z0 hour6 fol-lowed by treatment with water. For compound (124), hydrolysis can be accomplished by refluxing in trifluoroacetic acid for 0.2-1 hour6 or by catalytic hydrogenoly6i6 in the presence of a 6uitable catalyst such as 10% palladium on carbon. Deprotonation of (126) with a base, 6uch a6 60dium methoxide, 60dium hydride or the like in a 601vent 6uch a6 dimethyl-formamide or dimethylsulfoxide at room temperaturefollowed by alkylation with an appropriate benzyl halide at 25C for 2-20 hour6 afford6 ether6 of formula (127), as 6hown in equation a.
The 6ulfide (129) can be prepared from the thiophenol (45) by the procedure described above to prepare the ether (127) from the phenol (126). The thiophenol (45) can be prepared for example by treatment o~ the benzylsul~ide (128) with 60dium in liquid ammonia.
The amine (130) can be prepared as shown in equation c, from the aniline (63), itself available from reduction of the corresponding p-nitro compound (3a) which has previously been described. The reductive amination can be carried out by the same procedure as described in Scheme 13 for the preparation of compound (74).
Compounds of Formula (I) where the X linkage is -CH=CH-, -CH2CH2-, and are prepared as shown in Scheme ~Q -Scheme ~0 ~ PPh3 1_RR7 ~ R13 ~ R61Nj --CHO 131 ~3 N .R8 132 R6J~N~ RR7 X' 67 I 33409~
The ci6 or tran6 stilbene (132) can be obtained by employing a Wittig reaction between-the aldehyde (57) and the pho6phorane (131).
The 6tilbene (132) can readily be converted to the 6aturated derivative (133) for example by catalytic hydrogenation employing a heterogeneou6 cataly6t 6uch a6 palladium/carbon or platinum/carbon or alternatively with a homogeneou6 catalyst such a6 tri~triphenylpho6-phine rhodium chloride. The reduction ~6 performed in a 601vent such as benzene, tetrahydrofuran or ethanol at 25C under 1-3 atmo6pheres of hydrogen for 1-24 hour 6 .
The cyclopropane (134) can be prepared by treating the stilbene (132) with the Simmons-Smith reagent as de~cribed in J. Am. Chem. Soc., 81, 4256 (1959), or by treating (132) with methylene diiodide and copper powder as described in J. Am. Chem. Soc., 101, 2139 (1979), or by treatment with the iron-containing methylene-tran6fer reagent described in J. Am. Chem. Soc., 101, 6473 (1979).
The preparation of compound6 of formula (I) where X i6 -CF2CH2-, -CF.CH-, -CH~CF-, -CF.CF- and -CF2CF2- are depicted in Scheme 21.
Scheme 21 1 334 0 92 a) Ar8CH2Arl + Et2NSF3. CH2C12 ~ ArCF2CH2Ar ~35 \ / 136 ~ \~HF H+ ~1 0 ArCF= CHAr .~
b )ArCH2CAr + Et2NsF3 CH2C12 ArCH2CF2 138 \ / 139 ~,THF, H ~,/
ArCH= CFAr OOH
c)ArCCHArl + Et2NSF3 H2C12 ~ ArCF2CHFAr +
25141 \TIIF,H /A1203 142 ArCF = CFArl l43 d) A CC~l + Et NS~ ArCF2CF2Ar , ~v' . ~
Vinylene fluoride6 (137) and (140) can be pre-pared by reaction of SF4 or Et2NSF3 (DAST) with the appropriate ketone (135) or (138) in which Ar bears a methyl group convertible to a benzylic halide suitable for attachment to an imidazole nitrogen, and Ar' bear6 a cyano, nitro, e6ter, or other suitable group which can be ~ubsequently converted to CO2H, NHSO2CF3, etc.
The initially formed difluroethylene (136) and (139) can be formed in a non-polar solvent such as methylene chloride and sub6equently converted to the vinylene fluoride by means of alumina, or converted directly into the un6aturated fluoride by running the reaction in a polar sol~ent such a6 tetrahydrofuran, diglyme or N-methylpyrrolidone in the presence of mineral acid.
[Equations a and b]. Experimental details of such procedures are found in D.R. Strobach and G.A. Boswell, J. Orq. Chem., 36, B18 (1971): G.A. Boswell, U.S.
Patent6 3,413,321 (1968) and 4,212,515 (1980).
As 6hown in equation c an appropriate benzoin (141) may be 6imilarly converted to the corre6ponding 1,2-difluorostilbene (143). Likewise as shown in equation d an appropriate benzil (144) can be converted to a tetrafluorodiarylethylene (145) using DAST or SF4. Experimental detail6 are described in M.E.
Christy, et al., J. Med. Chem., 20, (3), 421-430, (1977).
Compound6 of formula 1 where X = -CON-, -CH2O-, -CH25-, -CH2NH-, can be made as 6hown in Scheme 22.
Scheme 22 1 334092 N-- R87 HN--ArR13--P N /R87 N-- R87 )R6--~N~ DCC, CH~CI7~ R6~N~ deprotect~n R61~ ~ R
HN--ArR13 ~q R23 ~ R23 ~C2Hp ,TsCI, pyr ~CON-ArR13-P CONArR13 P = protecting group (if necessary) ArR13 _ ~, ~ [~
~CO Me ~CH20H ~CH20Ts N--~ R7 K2CO3, DMF deprotection R6 N~
1~; HO-Ar-R13-p ~
153; HS-Ar-R13-P l~`XArR13 146; H2N-Ar-R13-P
154; X= -CH20-155; X= -CH2S-156; X= -CH2NH-As previously described, acid (10) can be made by alkylating the appropriate imidazole with methyl 4-chloromethylbenzoate in the presence of a base 6uch as potassium carbonate in a polar solvent 6uch a~
dimethylformamide followed by hydroly~i6 of the resulting ester. Compound (10) can be converted to (148) by reaction with the requi6ite amine (146) (R13 may need to be protected and 6ub6equently deprotected) and dicyclohexyl carbodiimide (DCC) in methylene chloride tJ. R. Beek, et al., J. Am. Chem. Soc, 90, 4706 (1968)~ or by reaction with to6yl chloride in pyridine tJ. H. Brew6ter and C. J. Ciotti, Jr., J. Am.
Chem. Soc., 77, 6214 (1955)]. Yet another proce66 involve6 conversion of carboxylic acid (10) to it6 acid chloride with, for example, thionyl chloride ollowed by reaction with the amine in aqueou6 base (Schotten-Baumann condition6) or in an organic 601vent in the pre6ence of an acid 6cavenger 6uch a6 NaHC03, pyridine or triethylamine, or by other procedure~
known to form an amide bond between an aromatic acid and an amine.
The compounds where X= -CH20-, -CH2S-, and -CH2NH2- can be made a6 6hown in pathway b. The ester (149) i6 reduced with a reducing agent 6uch a6 lithium aluminum hydride in an inert 601vent to form the alcohol (150) which can then be reacted with to6yl chloride in pyridine to form tosylate (151), which i6 in turn reacted in the pre6ence of ba6e with a corre6ponding-phenol (152) thiophenol (153), or aniline (~46: where R =H) to form compound6 (154), (155) or (156). Again thi6 may require that R13 be protected with a ~uitable protecting group, however modification6 necessary because of 6pecific functional groups are under6tood to be incorporated by one 6killed in the art of organic ~ynthesi6.
72 1 3~4~q 2 Alternatively, the alcohol (150) can be con-verted to the corresponding halide with SOC12, (COCl)2, etc, and the resulting halide can then be reacted with a phenol, thiophenol or aniline in the presence of base to $or~ the desired compound, where ~ i~
-CH2O-, -CH2S-, -CH2NH- respectively.
S cheme ~ 3 R23HN~ 1 3 3 4 0 9 2 a) N ~RR87 R1158, R N~
Base ~S~02 ~ ~RR87 CISO2~ N~R 7 b) R6N~ R13 1 ~
160 W~ N R23 N H R23 Base SO2 solvent Rl 8-.
- 1 3340~2 Compound6 of Formula (I) where X= -S02NR
and -NR23So2- may be prepared a6 shown in Scheme 23. A6 6hown in equation a, 6ulfonylchloride derivative (157) can be reacted with aniline derivative (158) in a solvent in the pre6ence of an acid 6cavenger 6uch as ~odium bicarbonate, triethy~a~ine or pyridine or under Schotten-Baumann like conditions to give (159). 5ulfonylchloride derivative (157) can be obtained by sulfonation of the corre6ponding benzyl derivative a~ de6cribed earlier, followed by reaction with PC15 or POC13. Likewi6e, aniline (74) may be reacted in the ~ame manner a~
de6cribed above with 6ulfonylchloride derivative (160) to give (161).
Scheme 24 6how6 the preparation of furan analog6 of the biphenyl compound6 (80). Thu6, a-ketoe6ter (162), W. Wierenga and H. I. Skulnick, J. Orq. Chem., 44, 310 (1979), or the corre6ponding nitrile (E.CN) can be ea6ily alkylated via 6tandard procedure6 already mentioned by an alkyl bromide derivative to give (163). The alkene moiety of (163) can be 6ub6equently cleaved by oxidation, for example, with 06mium tetroxide, Fie6er and Fie6er, V.l, p. 812 (Lemieux-John60n oxidation) to yield dicarbonyl-containing compound (164). Cyclization in mineralacid6, acidic ion-exchange re6in, POC13/pyridine, or trifluoroacetic anhydride with a catalytic amount of trifluoroacetic acid yield6 furan (165: Z.O).
Reaction of (164) with P4Slo, for example, will yield the corre6ponding thiophene (165; Z.S).
aeactiOn of (164) with an amine in refluxing benzene, with azeotropic removal of water or by u6ing ~olecular 6ieve6 to ab60rb the water will yield the corre6ponding pyrrole (165; Z-NR ). Compound6 (166) may be prepared from (165) by 6tandard procedure6 already de6cribed.
Scheme ~4 l 3 3 4 09 2 (Cl, 1, OTs, OMs, etc.~
E oS~ E
~R11 1~ E= CO2Me or CN R11 ~E ~ ~
Rll R11 O~ E
165 q~ R 11 E = CO2Me, CN R11 Z=O,S,NR1' N--~R7 ~OOH) (1 ~N ) R
166 Z = O, S, NR
t6 1 33409~
Compound6 wherein a methylene group is inserted between the terminal aromatic ring and the acidic functionality may be prepared a6 shown in Scheme 25, equation a). Thu6 reduction of e6ter (167) with, for example, lithium aluminum hydride, give6 alcohol (168). Conver6ion of (16~) to the chloride (169) via thionyl chloride followed by reaction with cyanide anion a6 previou61y de6cribed yield6 nitrile (170).
Compound (170) may be hydrolyzed to carboxylic acid (171) by method6 already de6cribed or reacted with a hydrazoic acid equivalent to produce tetrazole (172).
Compound6 wherein R i6 a trifluoromethyl6ul-fonyl hydrazide acidic functional group were prepared by the procedure de6cribed in equation b). That i6, conver6ion of e6ter (167) to the hydrazide (173) by standard hydrazinoly6i6 followed by reaction with triflic anhydride afford6 hydrazide6 (174).
Scheme 25 1 3 3 4 0 9 2 R6,l~ ~ R 1~ ~
~X C02Me ~X CH2oH
R61 ~ R6 1N , R
~ ~ ~ CHzCl (OTs, OMs, 3r, etc.~
~ ~
R61~ ~ R R6 ~ N ~
~ COOH ~ X ~ ~
R6 J~N~ R7 N ~ R8 ~ X O NH-NHZ ~ NHNHSOZCH3 173 ~ 174 i~ ~r .
- 1 3.j40~2 The 6yntheses of compound6 wherein Rl i6 sub~tituted and un6ubstituted l,2,3-triazole6 are described in Scheme 26. Thus reduction of e6ter (175) with a reducing agent 6uch a6 lithium aluminum hydride or diisobutylaluminum hydride give6 alcohol (176).
Oxidat-ion with MnO2 or pyridinium chlorochromate converts (176) into aldehyde (177). Nitroethylene derivative ~178) i6 prepared by conden6ation of aldehyde (177) with nitromethane in the presence of a catalyst, R. M. Letcher and M. P. Samme6, J. Chem.
Ed., 62, 262 (1985). Reaction of (178) with 60dium azide produce6 the 1,2,3-triazole (179), (N. S.
Zefirov, et al., J. Chem. Soc. Chem. Comm., 1001 (1971)) which may be transformed via procedure6 already de6cribed into product (180).
Aldehyde (177) can al60 be converted into sub6tituted 1,2,3-triazole6 (183) via the 6ulfone (181), G. Beck, D. Gunther, Chem. Ber., 106, 2758 (1973), followed by reaction with sodium azide to give the 1,2,3-triazole (182). Subsequent 6tandard manipulations lead to 1,2,3-triazole6 (183) where E=CN
and C02Rll. The nitrotriazole (183: E.N02) may be synthe6ized from the unprotected triazole (179;
P=H) via nitration, R. H~ttel, et al., Chem. Ber., 88, 1586 (1955), C. L. Habraken and P. Cohen-Fernande6 J. Chem. Soc., 37 (1972), or from bromonitroethylene derivative (184), G. Kh. Khi6amutdinov, et al., Zh.
Orq. Khim., 11, 2445 (1975), by reaction with 60dium azide.
A variety of protecting group6 may be u6ed in the manipulation of the above triazole6, among6t which i6 the trityl group. Thi6 group ~ay be ea6ily attached by reaction of the triazole with triphenylmethyl bromide or chloride in an inert solvent such a~ methylene chloride in the pre6ence of an acid 6cavenger such a~ triethyl amine. The trityl -group may be later removed by stirring or refluxing in an acidic medium 6uch a6 trifluoroacetic acid/water.
HCl in methylene chloride, or acetic acid/water. The trityl group may al60 be hydrogenolyzed u6ing a noble metal catalyst 6uch a6 palladium and hydrogen.
Scheme 26 1 3340q2 R=CH OH X~
177: R = CHO . NO2 1 ) NaN3 2) protecbion \~X~ ~ Br \~
1) NaN3 1) NaN3 2) protecbon 2) protection ~I
X~ ~X~
1 82 ~ N R7 R6lNi~ N= R~ P
~~ E = cO2R11, CH, N2 P = protecting group The 6ynthe6i6 of trifluoromethyl-1,2,4-triazole6 (190) i6 depicted in Scheme 27. Acid chloride (186) i~ converted to amide (187) u6ing 6tandard procedure6 familiar to one 6killed in the art. A preferred protecting group i6 the 2-propionitrile group (PzCH2CH2CN). Thu~ (187; P=CH2CH2CN) can be 6ynthe6ized from (186) and *-aminopropionitrile under Schotten-Baumann like condition6, using aqueou6 ba6e in an organic 601vent to help solubilize (186) and (187). Amide (187) i8 converted to amidrazone (188) by reaction with PC15 or pho6gene to make an iminoyl chloride which then in turn i6 reacted with exce66 hydrazine. Amidrazone (188) i6 cyclized to the trifluoromethyl-1,2,4-triazole (189) with trifluoroacetic anhydride and then converted to 190 via bromination, alkylation and deprotection a6 previou61y de6cribed.
S cheme 2 7 1 3340~2 P = PROTECTING GROUP
,0, ,0, ~ ~ Fl7 ~,F3C-O-CCF3 R6 N~
N~ ~ pN
~r -Pertinent R group6 may be variou61y intro-duced by many procedure~ including tho6e de6cribed in Scheme 28 which de6cribe6 imidazole con6tcuction.
The R6 group~ 60 introduced may 6tand unchanged or may be further elaborated if appropriately function-alized, according to method6 familiar to tho6e 6killed in the art 6uch a6 are illu~trated in Scheme 28.
Scheme 28 1 334092 NH OEt HO~~OEt H2N~OCH3 1)EtOH ~
OCH32) aq HCI J H
HO
1 ) Protect/
~2) TsCI
~9 R5(CH2)mSH ~ R5(CH2)moH N~3 R5(CH2)mS R'O NaH R5(cH2)mo 194 R5(CH2)mBr 197 R = CPh3, S02Ph, CH3CHOC2H5 :L~2; R' = H ~; R' = Ts PDC
~3 R5(CH2)mNH2 ~Ph3P=CHR' N~3 R NaCNBH3 N J R
R5(CH2)mNH CHO R R~ ~
1 33409~
B L A N K
P A G E:
-1 33409~
B L A N K
P A G E
1 3340q2 - The 2-alkenylimidazole6 (?ol) can be prepared by bromination of the 2-alkylimidazole6 (199) followed by elimination of hydrogen bromide. The bromization i6 preferably accompli6hed by W-irradiation for 1-4 hour6 of imadoyole (199) and N-bromosuccinimide, in an inert 601vent, 6uch a6 carbon tetrachloride at 25C.
Treatment of the intermediate bromide (?) with a ba6e, 6uch a~ DBU, triethylamine, or pota66ium t-butoxide, afford6 the tran6 2-alkenylimidazole6 (201). Ci6 alkenyl derivative6 (?03) are prepared from the tran6 alkenyl compound6 by treatment with 06mium tetroxide and 60dium periodate to afford aldehyde6 (202) followed by Wittig reaction.
_- 88 Scheme ~ 9 R~ ~ R bromination ~--~ N;~
-J /v\J
~/-HBr R~N--~RR87 ~ ~ R7 OSO4 (cat) H
R1 NalO4 R3 R2 ~N~ ~/\= PPh3 /v\J
~Q~
R = alkyl, cycloalkyi ..~
89 1 3340q 2 Alternatively, R g~oups may be introduced by metallation of a protected imidazole or protected 2-methylimidazole followed by addition of an appro-priate electrophile a6 illu6t~ated in Scheme 30, equation6 a) and b). The product6 (alcohol6, e6ter6, halide6, aldehyde6, alkyl6) are 6uitable for further elaboration by method6 familiar to tho6e 6killed in the art. Metallation of imidazole6 i6 de6cribed in K.L. Xirk, J. Orq. Chem., 43, 4381 (1978); R.J.
Sundberg, J. Het. Chem., 14, 517 (1977): J.V. Hay et al., J. Orq. Chem., 38, 4379 (1973): B. Iddon, HeterocYcle6~ 23, 417 (1985).
Conden6ation of 2-methylimidazole and appropriate electrophile6 (equation b) with catalytic acid or base a6 de6cribed in A.R. Katritzky (~d.), "Comprehen6ive Heterocyclic Chemi6try", Vol. 5, p. 431, Perqamon Pre66, N.Y., 1984 afford6 product6 wherein R6 i6 alkenyl which are 6uitable for further elaboration.
~ - 9o Scheme 30 ; 33409~
a) <~ N~ 1) R6x ~ 6R~N~
R R 2)H+ H
~L ~ (where R7=R3=H) R= CPh3, SO2Ph b)~N~ nBuLi ~ <~ 2) H+ N
206 207 2Q~
1 ) RCHO
\ ZnCI2 \2) H+
\~ N~
~N
R~ H
~Q~
~ 91 1 334092 Various 2-substituted imidazoles can be prepar-ed by reaction of a protected 2-trimethylsilylimi~7ole with a suitable electrophile by the method described by F.H. Pinkerton and S.F. Thames, J. Het. Chem., 9, 67 (1972), which can be fkrther elaborated as desired.
Alternatively, R6 may also be introduced by nickel catalyzed cross-coupling of Grignard reagents with 2-(methylthio)imidazoles (Scheme ~1) as described by E. Wenkert and T.W. Ferreira, J. Chem. Soc., Chem.
Commun., 840, (1982); E. Wenkert et al., J. Chem.
Soc., Chem. Commun., 637, (1979); and H. SllE~lra and H. Takei, Bull. Chem. Soc. Japan, ~ 664 (1985).
The 2-(methylthio)imidazoles can be produced by the procedure described in German Patent No. 2,618,370 and the references cited therein.
Scheme 31 KNCS + RN ICHcH(OcH3)2 aq HCI~ HS~ CH31 CH3S ~ ~ R8 R6MgCi , R6 ~ ~ R8 R (Ph3P)2NiCI2 R
3 or 2~ NiCI2 (dppp) 213 , _ 1 33409~
A6 shown in Scheme6 32-35, elaboration of R8 can be accompli6hed by procedure6 de6cribed in Scheme6 3, 28 and 30b and by chain exten6ion reaction6 familiar to tho6e 6killed in the art in which R bear6 a reac-tive terminal functional group, e.g. -OH, halogen, -CHO, -C02R, -C02H, -CH~CH2,-NH2, -N02, -CN, -C.NH, OR
etc., or by degradation reaction6 ~uch a6 conversion of an e6ter to an acid or an al~ene to an aldehyde.
Specifically, the hydroxymethyl group can be activated for the di6placement reaction by reacting with thionyl chloride, PC15 or with carbon tetra-chloride/triphenylpho6phine to form a corre~ponding chloro derivative. By a 6imilar reaction bromo and iodo derivative6 can be obtained. The hydroxymethyl group can al60 be activated by forming the corre-6ponding p-toluene6ulfonate, methane6ulfonate and trifluoromethane 6ulfonate derivative6. The hydroxyl group can be converted to it6 corre6ponding fluoro compound by variou6 fluorinating agent6 6uch a6 DAST
a6 6hown in Scheme 32.
-. Sche,m2 32 R7 ~7 R 6~ N~OH 2 2 (CH2)r (CH2)r Rl~ Rl~R3 ~,, , _' o 15 ~ ZnI
6~<~50'CH3 eOH , R61N~ SH
20(CH2)r (CH2)r R 1~3 R1~3 215 ` 216 ., 94 1 3~4092 Also as 6hown in Scheme 32, the hydroxyl group can be converted to thiolacetic acid derivative (215), J. Y. Gauthier, Tet. Lett., 15 (1986), and to thiol derivative (216) by subsequent hydroly6i6.
l~he hydroxymethyl group on compound (17) can be readily oxidized to an aldehyde group by mean6 of manganese dioxide or ceric ammonium nitrate. The aldehyde gcoup will undergo chain exten6ion reaction6 such as the Wittig and Wittig-Horner reactions and enter into typical carbon-carbon bond forming reactions with Grignard and lithium reagent6 as well as with compound6 bearing activated methylene group6.
Alternatively, the hydroxymethyl group can be oxidized directly to an acid functionality which can in turn be converted to ester and amide derivatives. The ester6 and amides can be prepared directly from the aldehyde6 by manganese dioxide oxidation in the pre6ence of 60dium cyanide and an alcohol or amine, J. Am. Chem.
S_c., 90, 5616 (1968) and J. Chem. Soc. (C), 2355 (1971).
As shown in Scheme 33, the chlorine on compound (25) can be displaced by the anion of dialkyl malonate to give the corresponding malonate derivative (217).
The saponification of (217) with NaOH (or ~OH) give6 the corresponding diacid which can be decarboxylated to give the corre6ponding propionic acid derivative (218) by heating to 120C. Alternatively, (218) can be directly obtained by re~luxing (217) with a mineral acid such as HCl or sulfuric acid. The free acid (218) can be esterified by heating in a medium of the variou6 alcohols and a catalytic amount of mineral acids 6uch as HCl or sulfuric acid to give the corre6ponding esters (Zl9). Alternatively the esters can be obtained by reacting the free acid (21B) and the corresponding alcohols in the presence of coupling reagents ;uch as DDQ or EEDQ. A .s~mil~r reaction with various mono-substituted and disubstituted amines pro-duces the corresponding amldes (220). A similar reac-tion with various mercaptans produces the corresponding thioesters.
Scheme 33 R6l~ M0 ~< l~
N COOR R~ N COOR 1)NaOH(KOH) 2~
(CH2), R170H/H+ R61,~CooR17 R2 R3 Rl ~2)r ~ \R18R19NH R2 R3 R6~ CONR18R~9 (cH2)r R1 ~
~Q
A~ ~hown in Scheme 34, the chloro group on ~?5) can be displaced by the ~odium 6alt or pota66ium salt o the alkyl, aryl or arylalkyl mercaptan6 to give the corresponding ~ulfide derivatives (221). The amine derivative (222) can be obtained by treating (?5) with ammonia or with the corresponding mono-6ub~tituted amines. Alternatively, the chloro group may be di6-placed by 60dium azide to give an azide intermediate which upon reduction with H2 over a noble metal cata-lyst or with a reducing agent 6uch a6 chromou6 chloride(W. K. Warburton, J. Chem. Soc., 2651 (1961)) yield6 (222) where R and R are hydrogen. Thi6 amine can be 6ub6equently alkylated with alkyl halide6, or reductively alkylated with aldehyde6 and ketone6 to give alkyl derivative6 of (222). The amine6 (?22) are converted to the corre6ponding carbamate6 (?24), 6ulfonamide6 (225), amides (226) or urea6 (?27) by 6tandard procedure6 illustrated in Scheme 34 and familiar to one 6killed in the art. The nitro compound (223) can be obtained by the treatment of (25) with 60dium nitrite or pota66ium nitrite. The nitrate (228) may be ~ynthesized by treatment Of (?5) with AgN03, A. F. Ferri6, et al., J. Am. Chem. Soc., 75, 4078 (1953).
Scheme 34 1 3 3 4 ~ ~ 2 R6 l~CI R6 _~ONO2 (cH2)r AgNO3 (cH2)r R1 R~ R3 Rl R~R3 \ 22 M~ R11NH2 \~N2 R6--Y~SR R6 ~NHRll R N~
R1--2~)3 R1 RÇ~ 3 R1 R2~ 3 O
~ R1SO2C OH R10~ R7 N~NR oR10 ~N--c _ R10 I NR1 1 1CR1o O N O (CH2)r R1 ~z~ R3 Rt R~2/~3 R1 R`/~R3 . ~ ~
-- _ .
Scheme 34 (Con t) 1 3 3 4 0 9 2 5R10-N=c=o ` N;~ R11 0 Hl (cH2)r R1 ~
Scheme 35 R7 ~R6 ~ ~ (cH2)n R16 25z ~ 3~ (where R16 = alkyl, (R = pyndyl)cycloalkyl, -(CH2)pC6H5) The compounds of this invention and their prepa-ration can be understood further by the following exam-ples, which do not constitute a limitation of the invention. In these examples, unless otherwise indicated, all temperatures are in desrees centi_rade and parts and percentases are by weight.
~ . ~
99 1 33409~
Example 1 PART A: Preparation of 2-Butyl-4-chloro-1-(q-cyanobenzYl~-5-hydroxymethylimidazole To a 601ution of 2-butyl-4-chloro-5-~ydroxy-methylimidazole (prepared a6 de6cribed in U.S.
4,355,040; 3.56 g, 40 mmol, 1 eq) in 300 mL methanol was added dropwise a fre~hly prepared 60dium methoxide ~olution (0.92 g Na, 40 mmol, 1 eg, in 30 mL MeOH).
After 6tirring for O.S hour6, the methanol was removed in vacuo and the re~ultant glas6 wa6 di6601ved in 100 mL DMF. To thi6 mixture wa6 added a 601ution of a-bromo-~-tolunitrile (8.60 g, 44 mmol, 1.1 eq) in DM~ and the entire content6 stirred overnight under N2 at room temperature. The ~olvent wa6 then removed in vacuo and the re~idue di6601ved in 300 mL ethyl acetate and 300 mL H20. The layer6 were 6eparated and the aqueou6 layer wa6 extracted twice with 300 mL
portions of ethyl acetate. The organic layer6 were dried and evaporated and the crude product fla6h chromatographed over 6ilica gel in 1:1 hexane/ethyl acetate to give 6.83 g of one regioi60mer a6 a white 601id; m.p. 92.5-98Ø NMR (200 MHZ,CDC13) ~
7.65 (d, 2H, J= 8Hz); 7.13 (d, 2H, J= 8Hz): 5.30 (6, 2H); 4.46 (6, 2H); 2.49 (t, 2H, J= 7Hz): 1.59 (m, 2H);
1.28 (m, 2H); 0.84 (t, 3H, J= 7Hz). Mas6 Calcd. for C16H18N30Cl: 303.1138. Found: 303.1124.
Continued elution gave 3.56 g of the 6econd regioi60mer a~ a white 601id, li6ted below a6 the fir6t entry in Table 1.
The intermediates 6hown below were prepared or could be prepared in acco~dance with the procedure described in Example 1, Part A u6ing the appropriately substituted imidazole and benzyl halide a6 6tarting material.
-R7 1 3340~2 N~
R6~N~
~3_Rl ,, Rl R6 R7 R8 MP( 10 4-CN n-butyl CH20H Cl 98.0-100.0 4-N02 n-butyl Cl 2 56.8- 59.5 4-N02 n-butyl CH2H Cl 114.5-116.5 2-CN n-butyl Cl CH20H 93.0- 95.5 PART B: Preparation of 2-Butyl-4-chloro-1-(4-cYanobenzyl)-5-cyanomethylimidazole Thionyl chloride (3.60 mL. 49 ~mol. 5 eq) was 610wly dripped into a ~olution of 2-butyl-4-chloro-1-(4-cyanobenzyl)-5-hydroxymethyl~imidazole (3.0 g, 9.9 mmol, 1 eg) in a minimum of CHC13. The mixture wa6 6tirred for 2 hour6 at room temperature after which the 601vent was removed in vacuo and the re6idue 6uspended in toluene (200 mL). The toluene wa6 removed on the rotary evaporator and thi6 procedure wa6 repeated again to remove all trace6 of thionyl chloride. The chloride wa6 then di6601ved in DMS0 (minimum to di6601ve) and added to a 601ution of sodium cyanide (2.90 g, 59 mmol, 6 eq) in DMS0 (200 mL). The 601ution wa6 6tirred overnight under N2 at room temperature after which 500 mL H20 wa6 added and the aqueou6 layer wa6 extracted three time6 with 300 mL of ethyl acetate.
The organic layer6 were dried and concentrated and the re6idue fla6h chromatographed in 4:1 hexane/ethyl acetate over 6ilica gel to give 1.62 g of a light yellow 601id; m.p. 109.5-113.0 NMR (200 MHz, CDC13) 7.70 (d, 2H, J= lOHz): 7.12 (d, 2H, J= lOHz); 3.51 101 1 3340q2 (s, ZH); 2.60 (t, 2H, J= 7Hz) 1.70 (m, 2H): 1.40 (m, 2H); 0.90 (t, 3H, J= 7Hz). Mass spectrum shows M =
312~314. Mass Calcd. for C17H17ClN4: 312.1139, Found 312.1126.
The intermed~ates shown below were prepared, or could be prepared, in accordance with the procedure described in Example 1, Part B using the appropriately substituted imidazole and benzyl balide as starting material.
R6lN~R8 ~ Rl R R R R MP(C) 20 4-CN n-butyl C 2 Cl (oil) 4-N02 n-butyl Cl 2 117.0-119 4-N02 n-butyl 2 Cl (oil) 2-CN n-butyl Cl CH2CN (oil) 3-CN n-butyl Cl 2 (oil a NMR (200 MHz, CDC13) ~ 7.66 (d, 2H, J= 7Hz);
7.12 (d, 2H, 2, J= 7Hz); 5.15 (s, 2H); 3.69 (s, 2H), 2,56 (t, 2H, J= 7Hz); 1.62 (t of t, 2H, J=
7,7Hz); 1.33 (t of q, 2H, J= 7,7Hz); 0.87 (t, 3H, J= 7Hz).
b NMR (200 MHz, CDC13) ~ 8.24 (d, 2H, J=
lOHz); 7.18 (d, 2H, J= lOHz); 5.20 (s, 2H);
3.67 (s, 2H); 2.55 (t, 2H, J= 7Hz); 1.64 (m, 2H); 1.34 (m, 2H); 0.85 (t, 3H, J= 7Hz).
102 1 3340q~
c NMR (200 MHz, CDC13) ~ 7.80 (d, lH, J=
lOHz): 7.64 (d of d, lH, J= lO,lOHz): 7.53 (d of d, lH, J= lO,lOHz); 6.74 (d, lH, J=
lOHz); 5.37 (s, 2H); 3.64 (s, 2H); 2.55 (t, 2H, J= 7Hz); 1.67 (m, 2H): 1.34 (m, 2H):
0.85 (t, 3H, J= 7Hz).
d NMR (200 MHz, CDC13) ~ 7.66 (d, lH, J=
7Hz): 7.54 (d of d, lH, J. 7,7Hz); 7.33 (~, lH); 7.25 (d, lH, J. 7Hz); 5.25 (6, 2H);
3.56 (s, 2H): 2.61 (t, 2H, J= 7Hz): 1.69 (m, 2H): 1.35 (m, 2H): 0.91 (t, 3H, J= 7Hz).
PART C: Preparation of 2-Butyl-1-(4-carboxybenzyl)-4-chloroimidazole-5-acetic acid 2-Butyl-4-chloro-1-(4-cyanobenzyl)-5-(cyano-methyl)imidazole (0.5 g) and a solution of 1:1 12 N
HCl/glacial acetic acid (10 mL) were mixed and refluxed for 6 hour~. The solvent6 were removed by rotary evaporation and the resultant solids were washed with isopropanol, and filtered. The mother liquor was flash chromatographed on silica gel in 1:1 hexane/ethyl acetate to give 60 mg of product. Further flushing of the column with isopropanol followed by preparatory TLC of the evaporated residue gave an additional 100 mg of product. NMR (200 MHz, DMS0-d6) ~ 7.90 (d, 2H, J= 8Hz); 7.12 (d, 2H, J=
8Hz); 5.30 (s, 2H); 3.08 (s, 2H); 2.50 (t, 2H, J=
7Hz); 1.49 (m, 2H); 1.24 (m, 2H); 0.79 (t, 3H, J=
7Hz). Mass. Calcd. for C13HlgClN2O4:
350.1033. Found 350.1066.
Example 2 1 3340~2 PART A: Preparation of 2-Butyl-4-chloro-1-(4-nitrobenzYl)imidazole-5-acetic acid 2-Butyl-4-chloro-5-(cyanomethyl)-1-(4-nitro-s benzyl)imidazole (7.08 g) and a 1:1 mixture of 12 N
HCl and glacial acetic acid (175 mL) were mixed and refluxed for 6 hour6. The 601vent6 were removed by rotary evaporation and water (300 mL) was then added to the residue. After a few minutes, the product precipitated and wa~ collected and dried to give 7.35 g of a solid: m.p. 207.0-210Ø NMR (200 MHz, D~SO-d6/CDC13) ~ 8.20 (d, 2H, J= lOHz): 7.22 (d, 2H, J= lOHz); 5.28 (s, 2H): 3.42 (6, 2H); 2.52 (t, 2H, J= 7Hz); 1.64 (m, 2H); 1.34 (m, 2H); 0.86 (t, 3H, J= 7Hz). Anal. Calcd. for C16H18ClN304; C, 54.63;
H, 5.16; N, 11.94. Found: C, 54.52; H, 5.05: N, 12.21.
PART B: Preparation of Methyl 2-butyl-4-chloro-1-(4-nitrobenzyl)imidazole-5-acetate 2-Butyl-4-chloro-1-(4-nitrobenzyl)imidazole-5-acetic acid (7.35 g, 20.9 mmol, leq); 3.1H HCl in dioxane (34.0 mL, 105.4 mmol, 5 eq) and 100 mL
methanol were mixed and refluxed for 7.5 ~ours. The solvents were removed by rotary evaporation and the re~idue taken up in methylene chloride and 1 N NaOH
(300 mL each). The layer~ were separated and the organic layer washed two more times with lN NaOH
(300 mL each), dried and concentrated to give 5.43 g of a light pin~ solid; m.p. 97.5-100Ø NMR (200 MHz, DMSO-d6) ~ 8.23 (d, 2H, Js 9Hz); 7.33 (d, 2H, J= 9Hz): 5.50 (~, 2H): 3.73 (6, 2H): 3.40 (s, 3H):
2.66 (t, 2H, J= 7Hz); 1.53 (m, 2H): 1.22 (m, 2H): 0.76 (t, 3H, J= 7Hz). Ma~s Calcd. for C17H20N304Cl:
365.1140. Found: 365.1158.
Methyl 2-butyl-S-chloro-1-(4-nitrobenzyl)-imidazole-5-acetate was al~o prepared by the procedure described in Example 2 Part B from 2-butyl-5-chloro-1-(4-nitrobenzyl)imidazole-5-acetic acid. NMR (200 MHz, CDC13) ~ 8.23 (d, 2H, J= lOHz); 7.20 (d, 2H, J= lOHz): 5.21 (6, 2H): 3.75 (c, 3H): 3.67 (8, 2H);
2.58 (t of t, 2H, J= 7Hz): 1.32 (q of t, 2H, J. 7Hz):
0.86 (t, 3H, J= 7Hz). Mass Calcd. for C17H20ClN304:
365.1142. Found 365.1132.
PART C: Methyl 2-butyl-4-chloro-1-(4-aminobenzyl)-imidazole-S-acetate A mixture of methyl 2-butyl-4-chloro-1-(4-nitro-benzyl)imidazole-S-acetate (S.00 g, 13.7 ~mol, 1 eq), iron (2.67 q, 47.8 ~mol, 3.5 eq), glacial ~cetic acid (5.47 mL, 95.3 mmol, 7 eq), and methanol (250 mL) wa~
refluxed for S.S hour~. The solvent was removed by rotary evaporation. The re~idue wa6 diluted with water (300 mL) and extracted five time6 with 300 mL
portions of ethyl acetate. The organic layers were dried and concentrated. The residue wa~ fla~h chromatographed in 75:25 hexane/ethyl acetate over 6ilica gel to qive 4.53 g of a golden yellow oil which crystallized after standing for several day~. NMR
(200 MHz, CDC13) ~ 6.72 (d, 2H, J= 7Hz); 6.60 (d, 2H, J= 7Hz): 4.99 (6, 2H): 3.61 (8, 3H): 3.47 (8, 2H):
2.60 (t, 2H, J= 7Hz): 1.68 (m, 2H): 1.35 (m, 2H): 0.86 (t, 3H, J= 7Hz). Mass 6pectrum showQ M~ . 335/337.
Ma~s C 1 . 17 22 3 2 335.1407.
The following intermediate~ were prepared by the procedure de~-cribed in Example 2, Part C from the corre6ponding nitro intermediates:
-N ~
R6~N~R8 ~Rl Rl R R R MP(C) 10 4-NH2 n-butyl CH2CO2CH3 Cl (oil) g-NH2 n-butyl ClOCOCH3 (oil) 4-NH2 n-butyl Cl 2 (oil) 15 a NMR (200 MHz, CDC13) ~ 6.85 (d, 2H, J=
7Hz): 6.63 (d, 2H, J= 7Hz); 4.95 (s, 2H);
3.69 (s, 3H); 2.57 (t, 2H, J= 7Hz); 1.59 (t of t, 2H, J= 7,7Hz): 1.30 ( t of q, 2H, Js 7,7Hz); 0.86 (t, 3H, J= 7Hz).
20 b NMR (200 MHz, CDC13) ~ 6.74 (d, 2H, J=
lOHz): 6.60 (d, 2H, J= 10Hz); 4.97 (s, 2H);
4.95 (s, 2H); 3.56 (t, 2H, J= 7Hz); 1.86 (s, 3H); 1.64 (t of t, 2H, J= 7,7Hz); 1.33 (t of q, 2H, J= 7,7Hz); 0.85 (t, 3H, J= 7Hz).
25 c NMR (200 MHz, CDC13) ~ 6.80 (d, 2H, J=
10Hz); 6.69 (d, 2H, J= 10Hz); 5.05 (s, 2H);
4.43 (s, 2H); 2.56 (t, 2H, J= 7Hz); 1.56 (t of t, 2H, J= 7,7Hz); 1.26 (t of q, 2H, J=
7,7Hz); 0.83 (t, 3H, J= 7Hz).
106 1 3340~2 PART D: Preparation of Methyl 2-butyl-1-t4-(2-carboxybenzamido)benzyl~-4-chloro-imidazole-5-acetate A chloroform solution (10 mL) of methyl 2-butyl-4-cbloro-1-(4-aminobenzyl)imidazole-5-acetate (500 mg, 1.5 mmol, 1 eq) wa6 mixed with a chloroform 601ution (10 mL) of p~thalic anhydride (221 mg, 1.5 mmol, 1 eq).
After five minute6 of stirring at room temperature, product began to precipitate. After 24 hour6, the product wa6 filtered, waEhed with a minimum amount of CHC13 and dried to give 400 mg of a white 601id.
After some evaporation, the mother liquor yielded an additional 220 mg of product, both of which ~ad identical melting point6: m.p. 109.5 - 112.5. NMR
(200 MHz, DMSO-d6) ~ 10.37 (S, lH): 7.85 (d, 2H, J= 8Hz): 7.71-7.50 (m, 5H): 6.96 (d, 2H, J= 10Hz):
5.12 (6, 2H): 3.60 (8, 2H): 3.49 (6, 3H): 2.55 t, 2, J= 7Hz): 1.52 (m, 2H): 1.27 (m, 2H): 0.83 (t, 3H, J=
7Hz). The carboxylic acid could be titrated with 1.000 N NaOH to form the 60dium 6alt. High re601ution ma66 6pectrum 6how6 M-18 (1066 of H20). Calcd. Ma66 for C25H26ClN3O5: 465.1455. Found: 465.1440.
ExamPle25 PART A: Preparation of 2-Butyl-5-chloro-1-(4-nitrobenzyl)imidazole-4-acetic acid 2-Butyl-5-chloro-4-cyanomethyl-1-(4-nitrobenzyl)-imidazole (4.48 g) wa6 converted to the corre6ponding carboxylic acid by the procedure de6cribed in Example 2, Part A. No product precipitated upon the addition of water (300 mL) until the pH wa6 raised to about 3 with conc. ammonium hydroxide to liberate the imid-azole from it6 HCl 6alt. The precipitated 601id6 were amorphous and ethyl acetate (5 x 300 mL) wa6 u~ed to extract the product. Tbe organic layer6 were dried -107 l 334092 and concentrated to give 3.93 g of a yellow 601id.
Recrystallization from hexane/ethyl acetate gave 3.06 g of a white solid; m.p. = 138.0-139.5. NMR (200 MHz, CDC13) ~ 8.25 (d, 2H, Jz lOHz): 7.21 (d, 2H, S J= 10Hz): 5.23 (s, 2H): 3.30 (6, 2H): 2.63 (t, 2H, J=
7Hz): 1.63 (t of t, 2H, J= 7,7Hz); 1.32 (t of q, 2H, J= 7,7Hz): 0.87 (t, 3H, J= 7Hz). Anal. Calcd. for C16H18ClN3O4: C, 54.63: H, 5.16: N, 11.94. Found: C, 54.75: H, 5.29: N, 12.14.
PART B: Preparation of Methyl 2-butyl-1-14-(2-carboxybenzamido)benzyl]-5-chloro-imidazole-4-acetate 2-Butyl-5-chloro-1-(4-nitrobenzyl)imidazole-4-acetic acid (Part A) was carried on to methyl 2-butyl-l-t4-(2-carboxybenzamido)benzyl]-5-chloroimidazole-4-acetate: m.p. 150.5-152.5 by the procedure described in Example 2. NMR (200 MHz, DMSO-d6) ~ 13.00 (bs, lH):
10.40 (6, lH), 7.87 (d, lH, J= 8Hz); 7.67 (d, 2H, J= 8Hz): 7.71-7.52 (m, 3H): 7.02 (d, 2H, J= 8Hz): 5.13 (s, 2H): 3.61 (s, 3H): 3.52 (s, 2H): 2.59 (t, 2H, J= 7Hz): 2.53 (t of t, 2H, J= 7,7Hz): 1.28 (t of q, 2H, J= 7,7Hz): 0.82 (t, 3H, J= 7Hz). Has6 Calcd. for C25H26ClN3O5-H2O: 465.1455. Found, 465.1460.
ExamPle 4 PART A: Preparation of 2-n-Butyl-4-chloro-5-methoxy-methyl-1-(4-nitrobenzYl)imidazole 2-n-butyl-4-chloro-5-hydroxymethyl-1-(4-nitrobenzyl)imidazole (10.5 g, 32.4 mmol, 1 eq), conc.
sulfuric acid (26 mL) and methanol (300 mL) were mixed and refluxed overnight. The 601vent was removed in vacuo and the re~idue taken up in water (about 300 mL). The pH was adjusted to 5 with lN NaOH and then this aqueous portion extracted with ethyl acetate (3 x 250 mL). The organic layers were collected, dried (MgS04) and the ~olvent removed in vacuo to yield 11.57 g of an amber oil. NMR (200 MHz, CDC13) ~ 8.22 (d, 2H, J= 8Hz): 7.15 (d, 2H, J= 8Hz): 5.26 (~, 2H): 4.25 (s, 2H): 3.23 (6, 3H): 2.52 (t, 2H, J-7Hz): 1.64 (t of t, 2H, J= 7,7Hz); 1.28 (t of q, 2H, J= 7,7Hz); 0.81 (t, 3H, J= 7Hz). Anal. Calcd. for C16H20ClN303-(H20)o 5: C, 55.41: H, 6.10: Cl, 10.22.
Found: C, 55.21: H, 6.22: Cl, 9.92.
PART B: Preparation of 1-(4-Aminobenzyl)-2.n-butyl-4-chloro-5-(methoxYmethyl)imidazole To a 601ution of 2-n-butyl-4-chloro-5-methoxymetbyl-1-(4-nitrobenzyl)imidazole (11.22 g) in methanol (100 mL) under N2 was carefully added 1.0 g of 10~ palladium on charcoal. Hydrogen ga6 was then bubbled through the solution for 4 bour6. The solution was filtered through Celite~ and the solvent removed in vacuo to yield 9.23 g of an amber oil. NMR (200 MHz, CDC13) ~ 7.99 (6, lH): 6.78 (d of d, 4H, J= 5,5Hz): 5.05 (8, 2H): 4.24 (6, 2H): 3.27 (6, 3H): 2.59 (t, 2H, J= 7Hz): 1.62 (t of t, 2H, J=
7,7Hz): 1.32 (t of q, 2H, J= 7,7Hz): 0.84 (t, 3H,J=
Hz). . 16 23 3 Found: 307.1460.
PART C: Preparation of 2-Butyl-1-14-(2-carboxybenz-amido)benzyl]-4-chloro-5-(methoxymethyl)-imidazole The above compound was prepared from 1-(4-aminobenzyl)-2-n-butyl-4-chloro-5-(methoxymethyl) imidazole (3.00 g, 9.7 mmol, 1 eq) and phthalic anhydride (1.44 g, 9.7 mmol, 1 eq) using the procedure of Example 2, Part D. Work-up yielded 1.71 g of an off-white powder, which was washed with acetonitrile.
-log 1 33409~
The insoluble material was filtered and dried to yield 1.17 9 of a white powder: m.p. 165.5-166.5C. NMR
(ZOO MHz, DMSO-d6) ~ 13.01 (m, lH): 10.39 (6, lH):
7.87 (d, lH, J= 7Hz): 7.75-7.46 (m, 5H): 7.03 (d, 2H, J= 8H7); ~.16 (s, 2H); 4.30 tS. 2H); 3.20 (8, 3H):
2.54 (t, 2H, J= 7Hz); 1.54 (t of t, 2H, J= 7,7Hz);
1.30 (t of q, 2H, J= 7,7Hz): 0.83 (t, 3H, J= 7Hz).
Anal. Calcd. for C24H26ClN304:C, 63.22: H, 5.75: Cl, 7.78. Found: C, 63.54; H, 5.76; Cl, 7.58.
Examples 5-18 6hown in Table 1 were prepared or could be prepared by t~e procedures described in Examples 2-4 from the appropriately sub6tituted aniline derivative and a suitable anhydride or acid c~loride. Other solvents, such as benzene or et~yl acetate may be substituted for chloroform.
Table 1 1 3 3 4 0 9 . 5 o ~ ` NHCR
Ex. 6 No. R R R7 R8 ~ n-butyl Cl CH2 0 ~CH3 (oil)a o ~ -HO ~ n-butyl Cl CH2CO2CH3 138.0-141.0 N,O2 ~
HO ~ ~ n-butyl Cl CH2CO2CH3 184.0-186.0 ~ F
3 8 HO ~ ~ F n-butyl Cl CH2CO2CH3 169.0-170.5 HO ~ n-butyl Cl CH2CO2CH3 172.0-173.5 ~: , Table 1 (cont'd ) 1 3340~
No. _ R _ R8 MP(C~
10 ~ n-butyl Cl CH2OCCH3 140.0-144.5 O
11 ~ n-butyl Cl CH2C02CH3 129-131 H ~ CH3(H) CH3(H) lS 12 ~ n-butyl Cl CH2C02CH3 119-121 H0 ~
o H(CH3) ~ No2(H) I, n-butyl Cl CH2C02CH3 148-151 ~OCCH3 (H) n-butyl Cl CH2C02CH3 159-160 ~H( OCCH3 ) HO~ n-butyl Cl CH2C02CH3 175-176 or ~
Table 1 (cont~d.) 1 334092 No. _ R R R MP(C) Cl ~G ~ n-butyl Cl CH2C02CH3 199.0-200.0 HO ~1 ~ (DCHA 6alt) ~r , o Cl Cl 17 ~ n-butyl Cl CH20CH3 173.5-177.0 Il I
-O Cl H(OCH3) 15 18 ~ n-butyl Cl CH2C02CH3 151-153 HO ~
O OcH3(~) a NMR (200 MHz, CDC13) ~ 9.48 (bs, lH);
7.87-7.61 (m, 2H); 7.5-7.0g (m, 8H); 6.69 (d, 2H, J= 9Hz); 4.98 (s, 2H); 3.45 (s, 3H); 3.40 (s, 2H); 2.56 (m, 2H); 1.48 (m, 2H): 1.26 (m, 2H); 0.72 (t, 3H, J= 7Hz).
Example 19 Preparation of 2-Butyl-4-chloro-5-hydroxymethyl-1-(9-carboxybenzyl)imidazole The title compound was prepared from 2-butyl-4-chloro-S-hydroxymethyl-1-(4-cyanobenzyl)imidazole by the method described in Example 2, Part A. NMR (200 MHz, CDC13 ~ DMSO-d6) ~ 7.96 (d, 2H, J= 8Hz); 7.13 (d, 2H, J= 8Hz); 5.33 (6, 2H); 4.40 (E, 2H); 2.50 (t, 2H, J= 7Hz); 1.57 (t of t, 2H, J= 7,7Hz): 1.27 (t of q, 2H, J= 7,7Hz); 0.85 (t, 3H, J= 7Hz).
113 1 3 ~ 4 0 ~ ~
Preparation of 5-Acetoxymethyl-2-butyl-1-(4-carboxybenzYl)-4-chloroimida2ole 2-Butyl-1-(4-carboxybenzyl)-4-chloro-5-(hydroxy-methyl)imidazole (2.00 g, 6.2 ~mol, 1 eq), acetic anhydride (1.46 mL, 15.5 ~mol, 2.5 eq), triethylamine (2.59 mL, 18.6 mmol, 3 eq) and TH~ (S0 mL) were mixed and 6tirred for 3 day6. Water (200 mL) wa6 added to the 601ution and the mixture wa6 stirred for 0.5 hour6. The pH was lowered to 5 vith conc. HCl and the mixture extracted with ethyl acetate (3 x 100 mL).
The organic layer6 were dried (MgSO4) and concentrated to give 2.47 g of a brown oil. Thi6 product (2.16 g) was di6601ved in a minimum of ethyl acetate and dicyclohexylamine (DCHA) (1.18 mL, 1 eq) wa6 added and mixed. The ~olution wa~ allowed to 610wly evaporate overnight. The DCHA 6alt 60 obtained (1.43 g) wa6 6ubsequently taken up in ethyl acetate (100 mL) and wa~hed with 1 N HCl (3 x 100 mL), followed by brine.
The organic layer was dried (MgS04) and concentrated to give a yellow oil (670 mg). NMR (200 ~Hz, CDC13) 8.09 (d, 2H, J= lOHz): 7.05 (d, 2H, J= lOHz); 5.20 (s, 2H);4.98 (6, 2H); 2.58 (t, 2H, J= 7Hz); 1.82 (t of t, 2H, J= 7,7Hz); 1.33 (t of q, 2H, J= 7,7Hz); 0.86 (t, 3, J= 7Hz). Anal. Calcd. for C18H21ClN2O4:
C, 59.26; H, 5.80, N, 7.68. ~ound: C, 58.89: H, 6.17;
N, 7.39. Mass C 1 . 18 21 2 4 ~ound: 364.1167.
114 1 3340q 2 Example 21 Preparation of Methyl Z-butyl-4-chloro-1-t4-(trifluoro-methyl6ulfonamido~benzyl3imidazole-5-acetate A 601ution of triflic anhydride (0.88 mL, 5.2 5 mmol, 1 eq) in methylene chloride (S mL) was dripped into a 601ution of met~yl 2-butyl-1-(4-aminobenzyl)-4-chloroimidazole-5-acetate (1,74 ~, 5.2 ~mol, 1 eq) and triethylamine tl.44 mL, 10.4 ~mol, 2 eq) in 20 mL
of methylene chloride at -78C. The solution wa6 ~ept at -78C for 1 hour after which it wa6 allowed to warm to room temperature. After 24 hour6, the reaction wa6 quenched with water (100 mL) and the pH adju6ted to 5 with conc. HCl and the aqueou6 extracted with methylene chloride (5 x 100 mL). The organic layer6 were dried (MgS04), concentrated, and the re6idue fla6h chromato-graphed in 1:1 hexane/ethyl acetate on 6ilica gel.
The cry6talline product which formed in the l:l hexane/
ethyl acetate solution while the crude product wa6 being applied to the column was i601ated (1.03 g).
Chromatography of the mother liquor yielded an additional 1.03 g of the title compound a~ a white 601id; m.p. 154.0-157Ø The product could be titrated with 1 equivalent of 1.000 N NaOH. NMR ~200 MHz, CDC13) ~ 7.32 (d, 2H, J= 10Hz: 6.91 (d, 2H, J= 10Hz); 5.15 (6, 2H): 3.62 (6, 3H): 3.46 (6, 2H):
2.55 (t, 2H, J= 7Hz): 1.56 (m, 2H): 1.26 (m, 2H): 0.72 (t, 3H, J=7Hz). Ma6s Calcd. for C18H21N3O4S~3Cl:
467.0890. Found: 467.0872.
Example6 22-25 in Table 2 were prepared or could be prepared by the procedure de6cribed in the above example employing the appropriately 6ub6tituted l-(aminobenzyl)-imidazole, which in 60me in6tance6 i6 followed by e6ter hydroly6i6 familiar to one 6~illed in the art.
Table 2 1 334092 R ~ N ~ R8 ~Rl Ex 1 R6R7 R8 MP(C) 22 NHSO2CF3 n-butyl Cl CH2H
23 NHSO2CF3 n-butyl Cl CH20CH3 24 NHS02CF3 n-butyl Cl CH2OCH2ÇH 3 NHS02CF3 n-butyl Cl CH2C02H (oil) a NMR (200 MHz, CDC13) ~ 7.29 (d, 2H, J=
lOHz); 6.64 (d, 2H, J= lOHz); 5.11 (s, 2H);
3.45 (s, 2H); 2.56 (t, 2H, J= 7Hz): 1.60 (m, 2H); 1.30 (m, 2H); 0.85 (t, 3H, J= 7Hz) Example 26 Preparation of 2-9utyl-4-chloro-5-t(lH-tetrazol-S-yl)methyll-1-~3-(lH-tetrazol-5-yl)benzyl]imidazole 2-Butyl-4-chloro-1-(3-cyanobenzyl)-5-(cyano-methyl)imidazole (2.00 g, 6.4 mmol, 1 eq); ammonium chloride (0.91 g, 17 mmol, 2.7 eq): sodium azide (1.11 g, 17 mmol, 2.7 eq) and DMF (25 mL) were mixed and stirred at 80C for 24 hours. The mixture was filtered and the solvent removed by rotary evapora-tion. The residue was dissolved in water (100 mL) and methy~ene chloride (100 mL). The layers were separated 116 1 3340~2 and the aqueous layer extracted again with methylene chloride (2 x 100 mL). The aqueous was then acidified with conc. HCl to pH of 3. The solid which precipi-tated was collected and dried to give 560 mg of the title compound as a tan solid: m.p. 254 (darken), 258 (dec.). The product when titrated with 1.000 N
NaOH showed the presence of exactly two acidic func-tionalities. M~R (200 MHz, DMSO-d6) ~ 8.79 (d, lH, J= 7Hz); 7.69 (s, lH); 7.53 (t, lH, J= 7Hz); 7.10 (d, lH, J= 7Hz); 5.37 (s, 2H); 4.23 (6, 2H); 2.57 (t, 2H, J= 7Hz); 1.53 (t of t, 2H, J= 7Hz); 1.27 (t of q, 2H, J= 7 Hz): 0.80 (t, 3H, J= 7Hz); Anal. Calcd. for C17HlgClNlo: C, 51.19; H, 4.80. Found: C, 51.04;
H, 4.69.
Example 27 Preparation of 2-Butyl-4-chloro-5-t(lH-tetrazol-5-yl)methyl]-l-tg-(lH-tetrazol-5-yl)benzyl]imidazole The title compound was prepared from 2-butyl-4-chloro-1-(4-cyanobenzyl)-5-(cyanomethyl)imidazole by the procedure described in Example 26; m.p. 228 (dark), 229.0-230 (dec). Titration with 1.000 _ NaOH showed the presence of exactly two acid functionalities. NMR
(200 MHz, DMSO-d6) ~ 7.95 (d, 2, J= 7Hz); 7.13 (d, 2, J= 7Hz); 5.34 (s, 2); 4.23 (s, 2); 2.53 (t, 2, J=
7Hz); 1.50 (t of t, 2, J= 7,7Hz); 1.26 (t of q, 2, J=
7Hz): 0.79 (t, 3, J= 7Hz); lR 3420 br, 1930 br, 740 cm . Mass Calcd. for C13HlgClNlo: 398.1482. Pound:
398.1509.
-117 1 3340q~
Example 28 Preparation of 2-Butyl-4-chloro-5-hydroxymethyl-1-(4-N-phthalimido~enzyl)imidazole 1-(4-Aminobenzyl)-2-butyl-4-chloro-5-(hydroxy-methyl)imidazole (1.00 g, 3.q mmol, 1 eq) in 20 mL of methylene chloride was dripped into a stirred ~olution of phthaloyl chloride (0.49 mL, 3.4 mmol, 1 eq), triethylamine (0.95 mL, 6.82 mmol, 2 eq) and methylene chloride (500 mL). After 11 days, the solvent was removed by rotary evaporation and the residue flash chromatographed in 1:1 hexane/ethyl acetate over silica gel to give 240 mg of the title compound as a light yellow glassy solid: m.p. 65.0-73.5, NMR (200 MHz, CDC13) ~ (key peaks only) 7.97 (m, 2H): 7.79 (m, 2H); 7.43 (d, 2, J= 10Hz): 7.11 (d, 2H, J= lOHz):
4.50 (s, 2H): 2.57 (t, 2H, J= 7Hz): 1.67 (m, 2H): 1.34 (m, 2H); 0.87 (t, 3H, J= 7Hz). Mass Calcd. for C23H22ClN3O3: 423.1349. Found: 423.1324.
ExamPle 29 Preparation of Methyl 2-butyl-4-chloro-1-(4-N-phthalimidobenzyl)imidazole-5-acetate Methyl 2-butyl-1-t4-(2-carboxybenzamido)benzyl]-4-chloroimidazole-5-acetate (1.00 g), methanol (50 mL) 25 and 3.6 mL of 3.1 N HCl in dioxane were refluxed for 6 days. The solvent was removed in vacuo and the residue taken up in ethyl acetate (100 mL). The organic phase was washed with 1 N NaOH (2 x 100 mL) and brine (1 x 100 mL), dried (MgSO4) and concentrated. The residue was flash chromatographed over silica qel in 75:25 hexane/ethyl acetate to give 400 mg of an oil which eventually crystallized; m.p. 141.5 - 143Ø NMR
(200 MHz, CDC13) ~ 7.92 (m, 2H): 7.80 (m, 2H); 7.43 (d, 2H, J= 10Hz); 7.08 (d, 2H, J= 10Hz); 5.17 (s, 2H);
3.62 (s, 3H); 3.50 (s, 2H); 2.62 (t, 2H, J= 7Hz); 1.71 -118 1 3340~2 lt of t, 2H, J= 7,7Hz): 1.36 (t of q, 2H, J= 7,7Hz);
0 89 (t, 3H, J= 7Hz). Mass Calcd. for C25H24ClN304:
465.1455. Found: 465.1440.
Example 30 Preparation of Methyl 2-butyl-4-chloro-1-t4-((N-trifluoromethane6ulfonyl)anthranilamido)ben2yl]-imidazole-5-acetate ~ethyl-1-(4-aminobenzyl)-2-butyl-4-chloro-5-imidazoleacetate (1.00 g, 2.98 mmol, 1 eq), N-(tri-fluoromethanesulfonyl)anthranoyl chloride which i~
described in EP 003836, (0.86 g, 2.99 mmol, 1 eq), and 60dium bicarbonate (1.25 g, 14.9 mmol, 5 eq) were mixed and stirred in 50 mL methylene chloride (acid chloride was added la6t). The reaction wa6 wor~ed up after 2.5 hour6 by filtering, removing the solvent from the filtrate in vacuo and recry6tallizing t~e residue from ethyl acetate/hexane to give 1.07 g of light yellow cry6tal6: m.p. 151.0 - 152Ø NMR (200 MHz, CDC13) ~ 9.32 (6, lH); 8.02 (d, lH, J5 lOHz);
7.79 (d, lH, J= lOHz): 7.56 (d of d, 2H, J= 10, lOHz):
7.50 (d, 2H, J= lOHz): 7.78 (d of d, lH, J= 10, lOHz):
6.86 (d, 2H, J= lOHz): 5.10 (6, 2H): 3.58 (6, 3H) 3.45 (6, 2H): 2.45 (t, 2H, J= 7Hz): 1.52 (t of t, 2H, J= 7,7Hz): 1.22 (t of q, 2H, J= 7,7Hz): 0.75 (t, 3H, J= 7Hz). Titration of the product with 1.000 _ NaOH
shows the presence of exactly one acidic function-ality. Anal. Calcd. for C25H26ClP3N405S: C, 51.15: H, 4.46: N, 9.54. Pound: C, 50.95: H, 4.26: N, 9.67.
Mass Calcd. for C25H26ClF3N405S: 586.1264. Pound:
586.1222.
119 i 334052 Example 31 Preparation of 2-Butyl-4-chloro-1-t4-((N-trifluoro methanesulfonyl)anthranilamido)benzyl~imidazole-5-acetic acid Methyl 2-butyl-4-chloro-1-~4-((N-trifluoro-methanesulfonyl)anthranilamido)benzyl~imidazole-5-acetate (400 mg, 0.66 mmol, 1 eq) wa6 stirred in 1.0 N
NaOH (0.66 mL, 0.66 mmol, 1 eq) for 3 hour6 under N2.
The pH wa~ adju6ted to 5 with 1.0 N HCl and the product precipitate wa6 collected and dried affording 120 mg of the title compound a6 a white colid. The NMR 6pectrum 6how6 the methyl e6ter to be mi66ing.
~a66 6pectrum 6how6 M-CO2 pea~. Ma66 Calcd. for C23H24C1~3N4O3S: 528.1209. Pound: 528.1236.
ExamPle 32 Preparation of 2-Butyl-l-t4-(2-carboxybenzamido)-benzYl~-4-chloroimidazole-s-acetic acid The title compound wa6 prepared from methyl 2-butyl-1-[4-(2-carboxybenzamido)benzyl~-4-chloroimid-azole-5-acetate by the procedure de6cribed in Example 31: m.p. 170.5 - 175Ø
Example6 33-53 in Table 3 were prepared or could be prepared by the procedure6 de6cribed in Examples 30 and 31 u~ing the appropriate aniline and acid chloride 6tarting mat,erial6.
Ta112e 3 1 3340~2 R ~ ~ ~ R
~ ~HCR
~o. _ R R R ~P(-C) 33 ~ n-butyl Cl CH2C02CH3 (o~l) 34 ~ Cl n-butyl Cl CH2C02CH3 35~ I n-butyl Cl CH2C02CH3 226-228 Il ,J
CF3S02N'"~;~' 36 ~ n-butyl Cl CH2C02CH3 153-156 CF3So2N ~
37~ Br n-propyl Cl CH20H
CF3S02N ~
H
38 ~ Br n-hexyl H CH2C02CH3 ~ 1 Table 3 (cont'd.) Ex.
No.R R R R MP(C) 3ç ~ n-propyl Cl CH2H
40 ~ n-butyl Cl CH2C02CH3 C F3 S 02 N--~
41 ~ n-propyl Cl CH2C02CH3 CF3S02jN ~
H furyl 42 ~ n-butyl Cl CH20H
43 ~ CH3CH2CH=CH- Cl CH2H
44 ~ n-butyl Cl CH20COCH3 ~ ~ ,,NHS02CF3 45 ~ n-butyl Cl CH20COCH3 3 2H ~ n-butyl CH2C02H Cl Table 3 (cont'd. ) Ex . R6 R7 R8 MP ( C ) 47 ~n-butyl Cl CH2C02H
NHso2cF3 48 ~ n-butyl Cl n-butyl 49 ~ n-butyl CH2C02H Cl 50~ n-hexyl Cl CH2C02H
C~`3502~
51~ n-butyl Cl CH2 2 3 52~ n-butyl Cl CH ~ N'~
CF3S02- N~ n-propyl Cl a UMR (200 MHz, CDC13) ~ 8.69 (s, lH); 7.82 (S, lH); 7.75 (d, lH, J= 7Hz); 7.59 (d, 2H, J= 1OHZ); 7.55 (d, lH, J= 7HZ); 7.45 (t, lH, J= 7Hz~; 6.87 (d, 2H, J= lOHZ); 5.06 (S, 2H); 3.60 (5, 3H); 3.46 (5, 2H); 2.54 (t, 2H, J= 7HZ); 1.55 (t of t, 2H, J=
7,7Hz); 1.24 ( t of q, 2H, J= 7,7HZ); 0.78 (t, 3H, J= 7HZ).
ExamPle 54 PART A: Preparation of Ethyl n-heptylimidate hydro~hloride To a 601ution of caprylonitrile (30 g, 0.24 mol) in 25 mL of absolute ethanol cooled to 0 wa~ bubbled HCl ga~ (9.6 g, 0.26 mol). After 7 day6 at 0 the vi6cou6 601ution wa6 diluted with 250 mL of anbydrou6 ether and the precipitated product wa6 filtered with 6uction onto a coar6e frit and wa6hed liberally with ether before placing under a vacuum to remove re6idual 601vent. The product wa6 6tored under nitrogen at 0 to yield 22 g (44~) of a-white solid. N~R (200 MHz, DMSO-d6) ~ 4.40 (q, 2H, J= 7Hz): 3.30 (m, 4H): 2.45 (m, 4H): 1.40-0.75 (m, 12H). ~a66. Spec. 172 (M-Cl).
PART B: Preparation of 2-Heptyl-5-(hydroxymethyl)-imidazole In a high-pre66ure (bomb) reactor wa6 placed ethyl n-heptylimidate hydrochloride (22 g, 0.11 mol), 1,3-dihydroxyacetone dimer (9.5 g, 0.053 mol) and liquid ammonia (60 g, 3.5 mol). The reactor wa6 6ealed and heated to 70 for 12 hour6. The crude product (24.7 g) wa~ purified by fla6h chromatography (6ilica gel, 300 g: 10:1 EtOAc/EtOH) to give 12.7 g (61%) of a light yellow 601id: m.p. 82-84. NMR (200 MHz, CDC13/Acetone-d6) ~ 6.75 (6, lH): 4.50 (6, 2H):
4.50-4.25 (br 6, 2H): 2.60 (t, 2H, 8Hz): 1.75-1.60 (m, 2H): 1.40-1.15 (m, 8H): 0.95-0.75 (m, 3H). Ma66 Spec.
196, 167 (M-Et), 149 (M-Et-H20).
- I 3340~2 PART C: Preparation of 4-Chloro-2-heptyl-5-hydroxy-methylimidazole To a solution of 2-heptyl-5-(hydroxymethyl)-imidazole (10.0 g, 51 mmol) in EtOH/1,4-dioxane (1:1:
600 mL) was added N-chloro6uccinimide (7.9 g, 59 mmol). After being 6tirred for 1 hour at room temperature the solvent6 were removed on a rotary evaporator and the 601id re~idue was partitioned between ethyl acetate and vater ~300 mL each). The organic phase was wa6hed with vater (150 mL), dried (MgSO4), filtered and concentrated to afford 12.4 g crude product. Recrystallization (1:1 EtOAc~hexane, 60 mL) gave 5.7 g (45%) of vhite cry6tal6: m.p.
134-140. NMR (200 MHz, CDC13~CD3OD) ~ 4.50 (6, 2H) 4.00-3.80 (br 6, 2H); 2.65 (t, 2H, 5Hz);
1.80-1.60 (m, 2H); 1.40-1.20 (m, 8H); 0.90-0.80 (m, 3H). Ma6s Spec. 230.
PART D: Preparation of 4-Chloro-2-heptyl-5-(hydroxy-methYl)-l-(4-nitrobenzyl~imidazole To a solution of 4-chloro-2-heptyl-5-(hydroxy-methyl)imidazole (5.2 g, 20.7 mmol) in dry DM~ (100 mL) wa6 added anhydrou6 K2CO3 (4.3 g, 31.1 mmol) followed by 4-nitrobenzylbromide (5.4 q, 24.9 mmol). The solu-tion wa6 6tirred 3-5 hour6 at 65-70. The reaction mixture wa6 poured into a separatory funnel containing EtOAc and H2O (300 mL each). The agueou6 phase wa6 extracted with EtOAc (150 mL) and the combined organic phase6 were wa6hed three time6 with H2O (150 mL) before being dried (MgSO4), filtered and concentrated to give 9.0 g brown crude oil. Chromatography (silica gel, 450 g: 1:1 EtOAc/hexane6) gave 1.3 g (17% overall, 35S
of theoretical); m.p. 110-115. NMR (200 MHz, CDC13) ~ 8.20 (d, 2H, 5Hz); 7.20 (d, 2H, 5Hz): 5.35 (s, 2H);
4.45 (~, 2H): 3.10-3.00 (m, lH): 2.50 (t, 2H, 5Hz):
-125 1 3340~2 1.75-1.50 (m, 2H): 1.40-1.10 (m, 8H); 0.90-0.75 (m, 3H). Mass Spec. 365.
PART E: Preparation of 1-(4-Aminobenzyl)-4-chloro-2-heptyl-5-hydroxymethylimidazole To a 601ution of 4-chloro-2-heptyl-S-hydroxy-methyl-1-(4-nitrobenzyl)imidazole (1.00 g, 2.7 mmol) in EtOH (30 mL) and qlacial acetic acid (5 mL) wa6 added iron powder (2.5 g, 44.8 mmol). The mixture was 6tirred while being refluxed for 20 minute6. The 601ution wa6 cooled, the iron wa6 removed by filtra-tion, and the 601ution wa6 partitioned between EtOAc and 20% aq. K2C03 (150 mL each). The organic phase wa6 wa6hed with 6aturated agueou6 NaCl, dried (MgS04), filtered and concentrated to afford 0.8 g yellow-orange oil. Fla6h chromatography (silica gel, 25 q:
EtOAc/hexane6, 1:1) gave 0.74 g (80~) of yellow-orange oil. NMR (200 MHz, CDC13) ~ 6.80-6.60 (ABq, 4H, 7Hz,32Hz): 5.10 (6, 2H): 4.45 (6, 2H): 3.75-3.60 (m, 20 ZH): 2.55 (t, 2H, 5Hz): 1.75-1.65 (m, 2H): 1.30-1.15 (m, 8H); 0.90-0.80 (m, 3H). Ma66 Spec. 335.
PART ~: Preparation of 4-Chloro-2-heptyl-5-hydroxy-methyl-l-t4-((N-trifluoromethane6ulfonyl)-anthranilamido~benzYllimidazole To a 601ution of 1-(4-aminobenzyl)-4-chloro-2-heptyl-5-(hydroxymethyl)imidazole (211 mg, 0.63 mmol) in dry methylene chloride (10 mL) wa6 added anhydrou6 60dium bicarbonate (263 mg, 3.1 mmol) followed by N-(trifluoromethanesUlfOnYl)anthranOYl chloride (180 mg, 0.63 mmol). After 2 hour6 the mixture wa6 filtered, the filtrate was concentrated and the residue was purified by fla~h chromatography (silica gel, 10 g; EtOAc) to provide 298 mg (81%) of pale yellow 601id; m.p. 90-95 (dec.). NMR (200 MHz, -CDC13~CD30D) ~ 7.75-6.80 (m, 8H); 5.10 (6, 2H):
4.gO (s, 2H); 2.50 (t, 2H, 7Hz); 1.75-l.S0 (m, 2H);
1.35-1.15 (m, 8H); 0.95-0.80 (m, 3H). Ma66 Spec - no mass ion observed due to apparent decomposition; 424 ( 2 3 3) Example 55 PART A: Preparation of Ethyl 3-methoxypropylimidate hYdrochloride This compound was prepared according to the procedure de6cribed in Example 54, Part A. Prom 3-methoxypropionitrile (30 g, 0.35 mol) and hydrogen chloride (14.1 g, 0.39 mol) in ethanol (25 mL) there wa6 obtained 37.7 g (64~) white solid. Has~ Spec. 132 lS (N-Cl).
PART B: Preparation of S-Hydroxymethyl-2-(2-methoxyethYl)imidazole This compound wa6 prepared according to the procedure described in Example 54, Part B. From etbyl 3-methoxypropylimidate (36.7 g, 0.22 mol), 1,3-dihyd-roxyacetone dimer (19.7 g, 0.11 mol) and liquid ammonia (90 g, 5.3 mol) there was obtained 14.0 g (41~) of an off-white 601id following chromatography, 25 m.p. 100-107. NMR (200 MHz, DMSO-d6) ~ 6.70 (6, lH); 4.30 (6, 2H): 3.6 (t, 2H, SHz): 3.20 (s, 3H):
2.80 (t, 2H, 5Hz). Mass Spec. 156.
PART C: Preparation of 4-Chloro-5-hydroxymethyl-2-(2-methoxYethyl~imidazole This compound wa~ prepared accordiDg to the procedure described in Example 54, Part C. From 4-hydroxymethyl-2-(2-methoxyethyl)imidazole (13.5 g, 81.7 mmol) and N-chlorosuccinimide (13.8 g, 103 mmol) was obtained 4.8 g (29~) of light yellow solid fol-lowing chromatography (6ilica gel, 500 q: EtOAc); m.p.102-108. NMR (200 MHz, CDC13/CD30D) ~ 4.50 (6, 2H); 3.65 (m, 4H); 3.40 (6, 3H); 2.90 (t, 2H, 5Hz).
Mas6 Spec. 190.
PART D: Preparation of 4-Chloro-5-~ydroxymethyl-2-(2-methoxyethyl)-1-(4-nitrobenzyl)imidazole Thi~ compound wa6 prepared according to the procedure de~cri~ed iD Example 54, Part D. Prom 4-chloro-5-hydroxymethyl-Z-~2-methoxyethyl)imidazole (4.3 g, 22.6 g) was obtained 2.2 9 (30S overall, 60%
of theoretical) of light yellow solid; m.p. 91-95.
NMR (200 MHz, CDC13) ~ 8.15 (d, 2H, 8Rz): 7.20 (d, 2H, 8Hz); 5.45 (8, 2H); 4.45 (6, 2H); 3.60 (t, 2H, 5Hz); 3.20 (6, 3H); 3.15 (6, lH); 2.80 (t, 2H, 5Hz).
Ma66 Spec. 325.
PART E: Preparation of 1-(4-Aminobenzyl)-4-chloro-5-hydroxYmethyl-2-(2-methoxyethyl)imidazole Thi6 compound wa6 prepared according to the procedure de6cribed in Example 54, Part E. Prom 4-chloro-5-hydroxymethyl-2-(2-methoxyethyl)-1-(4-nitrobenzyl)imidazole (2.2 g, 6.75 mmol) and iron powder (6.7 g, 120 mmol) there wa6 obtained 1.6 g (80%) of light yellow 601id; m.p. 164-167. NMR (200 MHz, CDC13/CD30D) ~ 6.80 (d, 2H, 7Hz); 6.65 (d, 2H, 7Hz): 5.15 (6, 2H): 4.45 (6, 2H): 4.30 (~, 3H):
3.60 (t, 2H, 5Hz); 3.25 (6, 3H): 2.8 (t, 2H, 5Hz).
Ma66 Spec. 295.
1 3340q2 PART F: Preparation of l-t4-(2-Carboxybenzamido)-benzyl]-4-chloro-5-hydroxymethyl-2-(2-methoxy-ethyl)imidazole To an acetonitrile 601ution (12 mL) of 1-(4-S aminobenzyl)-4-chloro-5-hydroxymet21yl-2-(2-methoYy-ethyl)imidazole (150 mg, 0.51 mmol) wa6 added an acetonitrile solution (2 ~L) of phthalic anhydride (75 mg, 0.51 mmol). After stirrinq overnight at room temperature a light yellow precipitate wa~ produced.
The mixture was cooled to 0, filtered with ~uction onto a fine fritted funnel and the solid wa6 wa~hed wit~ cold acetonitrile, chloroform and finally ether (2 mL each) to afford 180 mg (80~) of light tan 601id, m.p. 185-186 (dec.). NMR (200 MHz, CDC13/CD30D) ~
8.05-6.95 (m, 8H); 5.30 (s, 2H): 4.50 (6, 2H): 3.60 (t, 2H, 5Hz): 3.25 (6, 3H): 2.8 (t, 2H, 5Hz). Mas6 spec Calcd- for C22H18ClN33 (M 2H2 ) Found: 407.1031.
ExamPle 56 Preparation of 4-Chloro-5-~ydroxymethyl-2-(2-methoxy-ethyl)-l-t4-((N-trifluoromethane~ulfonyl)anthranil-amido)benzYllimidazole Thi6 compound wa~ prepared according to the procedure de6cribed in Example 54, Part F. From 1-(4-aminobenzyl)-4-cbloro-5-hydroxymethyl-2-(2-methoxyethyl)imidazole (200 mg, 0.68 mmol), N-(tri-fluoromethanesulfonyl)anthranoyl chloride (190 mg, 0.68 mmol) and 60dium bicarbonate (280 mg, 3.3 mmol) in acetonitrile (5 mL) wa6 obtained 300 mg (81~) of tan 601id after chromatography (6ilica gel, 20 g:
EtOAc/EtOH, 20:1); m.p. 75-95 (slow dec.) one 6pot by TLC. NMR (200 MHz, CDC13~CD30D) ~ 8.00-6.80 (m, 8H); 5.15 (~, 2H): 4.45 (~, 2H); 3.60 (t, 2H, 5Hz); 3.15 (s, 3H); 2.75 (t, 2H, 5Hz).
1 33409~
The following compound6 li6ted in Table 4 were prepared by the procedure~ de~cribed in Example6 54.
Parts D, E and 54, Part F or 55, Part F.
Table ~
lo a6~ 3 ~x .
No. R ~ MP(-C) 57 ~ ethyl (amorphou6 601id) CF3S02N ~
58 ~ i-propyl (a~orphous 601id)b S9 ~ n-butyl tamorPhou6 601id)C
~ n-pe~tyl (amorphou6 601id)d CF3 02H CH2 (amorphou6 601 id)e 62 ~ ethyl 188-189.5 H02C (free acid) ~- 130 1 334092 Table 4 ( continued) Ex.
No. R R6 MP(C) 63 ~ n-propyl 181.5-183 HO2C (free acid) 64 ~ n-butyl 188.5-189.5 HO2C (Na+salt) ~ n-pentyl 170.5-171.5 66 ~ n-hexyl 171-171.5 67 ~ n-heptyl 181-182 69 ~ ~CH2 ~ CH3O-~-CH2 150-152 71 ~ ~CH2 175 - 177 X.
a NMR ~ 8.05 (d, lH); 7.62 (d, 2H): 7.52 (d, lH); 7.30 (t, lH); 7.17 (m, 3H); 6.93 (m, 2H):
5.13 (s, 2H): 2.61 (quart., 2H); l.lS (t, 3H).
b NMR ~ 8.04 (d, lH); 7.63 (d, 2H); 7.51 (d, lH); 7.2~ (t, lH); 7.13 (m, 3H); 6.89 (m, 2H);
5.14 (~, 2H); 3.11 (~ept., lH); 1.11 (d, 6H).
c NMR ~ 8.05 (d. lH); 7.64 (d, 2H); 7.52 (d, lH); 7.30 (t, lH); 7.17 (m, 3H); 6.92 (m, 2H);
5.15 (6, 2H); 2.66 (t, 2H): 1.53 (quint.. 2H):
1.28 (6ext., 2H): 0.83 (t, 3H).
d NMR ~ 8.07 (d, lH): 7.68 (d, 2H): 7.52 (m, 2H); 7.30 (m, 4H); 6.93 (t, lH); 5.29 (~, 2H);
2.83 (t, 2H); 1.56 (m, 2H); 1.24 (m, 4H); 0.82 (t, 3H).
e NMR ~ 8.03 (d, lH); 7.61 (d, 2H); 7.51 (d, lH); 7.28 (t, lH); 7.10 (m, 3H); 6.91 (t, lH);
6.78 (~, lH); 5.09 (~, 2H); 2.46 (d, 2H); 1.62 (m, 6H); 0.99 (m, 5H).
-ExamPle 72 PART A: Preparation of 5-Hydroxymethyl-2-mercapto-1-(4-nitrobenzYl)imidazole A mixture of 4-nitrobenzylamine hydrochloride (75 g, 0.40 mol), 1,3-dihydroxyacetone dimer (32.1, 0.17 mol) and potassium thiocyanate (51.9 g, 0.53 mol) in n-butanol (250 mL) and glacial acetic acid (40 mL) was 6tirred vigorously at room temperature for 48 hour6.
The mixture wa6 suction filtered and the 601id was washed thrice with water (300 mL) and thrice with ether (300 mL) before beinq dried overnight under vacuum to give 70.9 g (75t) of a yellow tan powder:
m.p. 214-215 (dec.). NMR (200 MHz, DMSO-d6) ~
o H(CH3) ~ No2(H) I, n-butyl Cl CH2C02CH3 148-151 ~OCCH3 (H) n-butyl Cl CH2C02CH3 159-160 ~H( OCCH3 ) HO~ n-butyl Cl CH2C02CH3 175-176 or ~
Table 1 (cont~d.) 1 334092 No. _ R R R MP(C) Cl ~G ~ n-butyl Cl CH2C02CH3 199.0-200.0 HO ~1 ~ (DCHA 6alt) ~r , o Cl Cl 17 ~ n-butyl Cl CH20CH3 173.5-177.0 Il I
-O Cl H(OCH3) 15 18 ~ n-butyl Cl CH2C02CH3 151-153 HO ~
O OcH3(~) a NMR (200 MHz, CDC13) ~ 9.48 (bs, lH);
7.87-7.61 (m, 2H); 7.5-7.0g (m, 8H); 6.69 (d, 2H, J= 9Hz); 4.98 (s, 2H); 3.45 (s, 3H); 3.40 (s, 2H); 2.56 (m, 2H); 1.48 (m, 2H): 1.26 (m, 2H); 0.72 (t, 3H, J= 7Hz).
Example 19 Preparation of 2-Butyl-4-chloro-5-hydroxymethyl-1-(9-carboxybenzyl)imidazole The title compound was prepared from 2-butyl-4-chloro-S-hydroxymethyl-1-(4-cyanobenzyl)imidazole by the method described in Example 2, Part A. NMR (200 MHz, CDC13 ~ DMSO-d6) ~ 7.96 (d, 2H, J= 8Hz); 7.13 (d, 2H, J= 8Hz); 5.33 (6, 2H); 4.40 (E, 2H); 2.50 (t, 2H, J= 7Hz); 1.57 (t of t, 2H, J= 7,7Hz): 1.27 (t of q, 2H, J= 7,7Hz); 0.85 (t, 3H, J= 7Hz).
113 1 3 ~ 4 0 ~ ~
Preparation of 5-Acetoxymethyl-2-butyl-1-(4-carboxybenzYl)-4-chloroimida2ole 2-Butyl-1-(4-carboxybenzyl)-4-chloro-5-(hydroxy-methyl)imidazole (2.00 g, 6.2 ~mol, 1 eq), acetic anhydride (1.46 mL, 15.5 ~mol, 2.5 eq), triethylamine (2.59 mL, 18.6 mmol, 3 eq) and TH~ (S0 mL) were mixed and 6tirred for 3 day6. Water (200 mL) wa6 added to the 601ution and the mixture wa6 stirred for 0.5 hour6. The pH was lowered to 5 vith conc. HCl and the mixture extracted with ethyl acetate (3 x 100 mL).
The organic layer6 were dried (MgSO4) and concentrated to give 2.47 g of a brown oil. Thi6 product (2.16 g) was di6601ved in a minimum of ethyl acetate and dicyclohexylamine (DCHA) (1.18 mL, 1 eq) wa6 added and mixed. The ~olution wa~ allowed to 610wly evaporate overnight. The DCHA 6alt 60 obtained (1.43 g) wa6 6ubsequently taken up in ethyl acetate (100 mL) and wa~hed with 1 N HCl (3 x 100 mL), followed by brine.
The organic layer was dried (MgS04) and concentrated to give a yellow oil (670 mg). NMR (200 ~Hz, CDC13) 8.09 (d, 2H, J= lOHz): 7.05 (d, 2H, J= lOHz); 5.20 (s, 2H);4.98 (6, 2H); 2.58 (t, 2H, J= 7Hz); 1.82 (t of t, 2H, J= 7,7Hz); 1.33 (t of q, 2H, J= 7,7Hz); 0.86 (t, 3, J= 7Hz). Anal. Calcd. for C18H21ClN2O4:
C, 59.26; H, 5.80, N, 7.68. ~ound: C, 58.89: H, 6.17;
N, 7.39. Mass C 1 . 18 21 2 4 ~ound: 364.1167.
114 1 3340q 2 Example 21 Preparation of Methyl Z-butyl-4-chloro-1-t4-(trifluoro-methyl6ulfonamido~benzyl3imidazole-5-acetate A 601ution of triflic anhydride (0.88 mL, 5.2 5 mmol, 1 eq) in methylene chloride (S mL) was dripped into a 601ution of met~yl 2-butyl-1-(4-aminobenzyl)-4-chloroimidazole-5-acetate (1,74 ~, 5.2 ~mol, 1 eq) and triethylamine tl.44 mL, 10.4 ~mol, 2 eq) in 20 mL
of methylene chloride at -78C. The solution wa6 ~ept at -78C for 1 hour after which it wa6 allowed to warm to room temperature. After 24 hour6, the reaction wa6 quenched with water (100 mL) and the pH adju6ted to 5 with conc. HCl and the aqueou6 extracted with methylene chloride (5 x 100 mL). The organic layer6 were dried (MgS04), concentrated, and the re6idue fla6h chromato-graphed in 1:1 hexane/ethyl acetate on 6ilica gel.
The cry6talline product which formed in the l:l hexane/
ethyl acetate solution while the crude product wa6 being applied to the column was i601ated (1.03 g).
Chromatography of the mother liquor yielded an additional 1.03 g of the title compound a~ a white 601id; m.p. 154.0-157Ø The product could be titrated with 1 equivalent of 1.000 N NaOH. NMR ~200 MHz, CDC13) ~ 7.32 (d, 2H, J= 10Hz: 6.91 (d, 2H, J= 10Hz); 5.15 (6, 2H): 3.62 (6, 3H): 3.46 (6, 2H):
2.55 (t, 2H, J= 7Hz): 1.56 (m, 2H): 1.26 (m, 2H): 0.72 (t, 3H, J=7Hz). Ma6s Calcd. for C18H21N3O4S~3Cl:
467.0890. Found: 467.0872.
Example6 22-25 in Table 2 were prepared or could be prepared by the procedure de6cribed in the above example employing the appropriately 6ub6tituted l-(aminobenzyl)-imidazole, which in 60me in6tance6 i6 followed by e6ter hydroly6i6 familiar to one 6~illed in the art.
Table 2 1 334092 R ~ N ~ R8 ~Rl Ex 1 R6R7 R8 MP(C) 22 NHSO2CF3 n-butyl Cl CH2H
23 NHSO2CF3 n-butyl Cl CH20CH3 24 NHS02CF3 n-butyl Cl CH2OCH2ÇH 3 NHS02CF3 n-butyl Cl CH2C02H (oil) a NMR (200 MHz, CDC13) ~ 7.29 (d, 2H, J=
lOHz); 6.64 (d, 2H, J= lOHz); 5.11 (s, 2H);
3.45 (s, 2H); 2.56 (t, 2H, J= 7Hz): 1.60 (m, 2H); 1.30 (m, 2H); 0.85 (t, 3H, J= 7Hz) Example 26 Preparation of 2-9utyl-4-chloro-5-t(lH-tetrazol-S-yl)methyll-1-~3-(lH-tetrazol-5-yl)benzyl]imidazole 2-Butyl-4-chloro-1-(3-cyanobenzyl)-5-(cyano-methyl)imidazole (2.00 g, 6.4 mmol, 1 eq); ammonium chloride (0.91 g, 17 mmol, 2.7 eq): sodium azide (1.11 g, 17 mmol, 2.7 eq) and DMF (25 mL) were mixed and stirred at 80C for 24 hours. The mixture was filtered and the solvent removed by rotary evapora-tion. The residue was dissolved in water (100 mL) and methy~ene chloride (100 mL). The layers were separated 116 1 3340~2 and the aqueous layer extracted again with methylene chloride (2 x 100 mL). The aqueous was then acidified with conc. HCl to pH of 3. The solid which precipi-tated was collected and dried to give 560 mg of the title compound as a tan solid: m.p. 254 (darken), 258 (dec.). The product when titrated with 1.000 N
NaOH showed the presence of exactly two acidic func-tionalities. M~R (200 MHz, DMSO-d6) ~ 8.79 (d, lH, J= 7Hz); 7.69 (s, lH); 7.53 (t, lH, J= 7Hz); 7.10 (d, lH, J= 7Hz); 5.37 (s, 2H); 4.23 (6, 2H); 2.57 (t, 2H, J= 7Hz); 1.53 (t of t, 2H, J= 7Hz); 1.27 (t of q, 2H, J= 7 Hz): 0.80 (t, 3H, J= 7Hz); Anal. Calcd. for C17HlgClNlo: C, 51.19; H, 4.80. Found: C, 51.04;
H, 4.69.
Example 27 Preparation of 2-Butyl-4-chloro-5-t(lH-tetrazol-5-yl)methyl]-l-tg-(lH-tetrazol-5-yl)benzyl]imidazole The title compound was prepared from 2-butyl-4-chloro-1-(4-cyanobenzyl)-5-(cyanomethyl)imidazole by the procedure described in Example 26; m.p. 228 (dark), 229.0-230 (dec). Titration with 1.000 _ NaOH showed the presence of exactly two acid functionalities. NMR
(200 MHz, DMSO-d6) ~ 7.95 (d, 2, J= 7Hz); 7.13 (d, 2, J= 7Hz); 5.34 (s, 2); 4.23 (s, 2); 2.53 (t, 2, J=
7Hz); 1.50 (t of t, 2, J= 7,7Hz); 1.26 (t of q, 2, J=
7Hz): 0.79 (t, 3, J= 7Hz); lR 3420 br, 1930 br, 740 cm . Mass Calcd. for C13HlgClNlo: 398.1482. Pound:
398.1509.
-117 1 3340q~
Example 28 Preparation of 2-Butyl-4-chloro-5-hydroxymethyl-1-(4-N-phthalimido~enzyl)imidazole 1-(4-Aminobenzyl)-2-butyl-4-chloro-5-(hydroxy-methyl)imidazole (1.00 g, 3.q mmol, 1 eq) in 20 mL of methylene chloride was dripped into a stirred ~olution of phthaloyl chloride (0.49 mL, 3.4 mmol, 1 eq), triethylamine (0.95 mL, 6.82 mmol, 2 eq) and methylene chloride (500 mL). After 11 days, the solvent was removed by rotary evaporation and the residue flash chromatographed in 1:1 hexane/ethyl acetate over silica gel to give 240 mg of the title compound as a light yellow glassy solid: m.p. 65.0-73.5, NMR (200 MHz, CDC13) ~ (key peaks only) 7.97 (m, 2H): 7.79 (m, 2H); 7.43 (d, 2, J= 10Hz): 7.11 (d, 2H, J= lOHz):
4.50 (s, 2H): 2.57 (t, 2H, J= 7Hz): 1.67 (m, 2H): 1.34 (m, 2H); 0.87 (t, 3H, J= 7Hz). Mass Calcd. for C23H22ClN3O3: 423.1349. Found: 423.1324.
ExamPle 29 Preparation of Methyl 2-butyl-4-chloro-1-(4-N-phthalimidobenzyl)imidazole-5-acetate Methyl 2-butyl-1-t4-(2-carboxybenzamido)benzyl]-4-chloroimidazole-5-acetate (1.00 g), methanol (50 mL) 25 and 3.6 mL of 3.1 N HCl in dioxane were refluxed for 6 days. The solvent was removed in vacuo and the residue taken up in ethyl acetate (100 mL). The organic phase was washed with 1 N NaOH (2 x 100 mL) and brine (1 x 100 mL), dried (MgSO4) and concentrated. The residue was flash chromatographed over silica qel in 75:25 hexane/ethyl acetate to give 400 mg of an oil which eventually crystallized; m.p. 141.5 - 143Ø NMR
(200 MHz, CDC13) ~ 7.92 (m, 2H): 7.80 (m, 2H); 7.43 (d, 2H, J= 10Hz); 7.08 (d, 2H, J= 10Hz); 5.17 (s, 2H);
3.62 (s, 3H); 3.50 (s, 2H); 2.62 (t, 2H, J= 7Hz); 1.71 -118 1 3340~2 lt of t, 2H, J= 7,7Hz): 1.36 (t of q, 2H, J= 7,7Hz);
0 89 (t, 3H, J= 7Hz). Mass Calcd. for C25H24ClN304:
465.1455. Found: 465.1440.
Example 30 Preparation of Methyl 2-butyl-4-chloro-1-t4-((N-trifluoromethane6ulfonyl)anthranilamido)ben2yl]-imidazole-5-acetate ~ethyl-1-(4-aminobenzyl)-2-butyl-4-chloro-5-imidazoleacetate (1.00 g, 2.98 mmol, 1 eq), N-(tri-fluoromethanesulfonyl)anthranoyl chloride which i~
described in EP 003836, (0.86 g, 2.99 mmol, 1 eq), and 60dium bicarbonate (1.25 g, 14.9 mmol, 5 eq) were mixed and stirred in 50 mL methylene chloride (acid chloride was added la6t). The reaction wa6 wor~ed up after 2.5 hour6 by filtering, removing the solvent from the filtrate in vacuo and recry6tallizing t~e residue from ethyl acetate/hexane to give 1.07 g of light yellow cry6tal6: m.p. 151.0 - 152Ø NMR (200 MHz, CDC13) ~ 9.32 (6, lH); 8.02 (d, lH, J5 lOHz);
7.79 (d, lH, J= lOHz): 7.56 (d of d, 2H, J= 10, lOHz):
7.50 (d, 2H, J= lOHz): 7.78 (d of d, lH, J= 10, lOHz):
6.86 (d, 2H, J= lOHz): 5.10 (6, 2H): 3.58 (6, 3H) 3.45 (6, 2H): 2.45 (t, 2H, J= 7Hz): 1.52 (t of t, 2H, J= 7,7Hz): 1.22 (t of q, 2H, J= 7,7Hz): 0.75 (t, 3H, J= 7Hz). Titration of the product with 1.000 _ NaOH
shows the presence of exactly one acidic function-ality. Anal. Calcd. for C25H26ClP3N405S: C, 51.15: H, 4.46: N, 9.54. Pound: C, 50.95: H, 4.26: N, 9.67.
Mass Calcd. for C25H26ClF3N405S: 586.1264. Pound:
586.1222.
119 i 334052 Example 31 Preparation of 2-Butyl-4-chloro-1-t4-((N-trifluoro methanesulfonyl)anthranilamido)benzyl~imidazole-5-acetic acid Methyl 2-butyl-4-chloro-1-~4-((N-trifluoro-methanesulfonyl)anthranilamido)benzyl~imidazole-5-acetate (400 mg, 0.66 mmol, 1 eq) wa6 stirred in 1.0 N
NaOH (0.66 mL, 0.66 mmol, 1 eq) for 3 hour6 under N2.
The pH wa~ adju6ted to 5 with 1.0 N HCl and the product precipitate wa6 collected and dried affording 120 mg of the title compound a6 a white colid. The NMR 6pectrum 6how6 the methyl e6ter to be mi66ing.
~a66 6pectrum 6how6 M-CO2 pea~. Ma66 Calcd. for C23H24C1~3N4O3S: 528.1209. Pound: 528.1236.
ExamPle 32 Preparation of 2-Butyl-l-t4-(2-carboxybenzamido)-benzYl~-4-chloroimidazole-s-acetic acid The title compound wa6 prepared from methyl 2-butyl-1-[4-(2-carboxybenzamido)benzyl~-4-chloroimid-azole-5-acetate by the procedure de6cribed in Example 31: m.p. 170.5 - 175Ø
Example6 33-53 in Table 3 were prepared or could be prepared by the procedure6 de6cribed in Examples 30 and 31 u~ing the appropriate aniline and acid chloride 6tarting mat,erial6.
Ta112e 3 1 3340~2 R ~ ~ ~ R
~ ~HCR
~o. _ R R R ~P(-C) 33 ~ n-butyl Cl CH2C02CH3 (o~l) 34 ~ Cl n-butyl Cl CH2C02CH3 35~ I n-butyl Cl CH2C02CH3 226-228 Il ,J
CF3S02N'"~;~' 36 ~ n-butyl Cl CH2C02CH3 153-156 CF3So2N ~
37~ Br n-propyl Cl CH20H
CF3S02N ~
H
38 ~ Br n-hexyl H CH2C02CH3 ~ 1 Table 3 (cont'd.) Ex.
No.R R R R MP(C) 3ç ~ n-propyl Cl CH2H
40 ~ n-butyl Cl CH2C02CH3 C F3 S 02 N--~
41 ~ n-propyl Cl CH2C02CH3 CF3S02jN ~
H furyl 42 ~ n-butyl Cl CH20H
43 ~ CH3CH2CH=CH- Cl CH2H
44 ~ n-butyl Cl CH20COCH3 ~ ~ ,,NHS02CF3 45 ~ n-butyl Cl CH20COCH3 3 2H ~ n-butyl CH2C02H Cl Table 3 (cont'd. ) Ex . R6 R7 R8 MP ( C ) 47 ~n-butyl Cl CH2C02H
NHso2cF3 48 ~ n-butyl Cl n-butyl 49 ~ n-butyl CH2C02H Cl 50~ n-hexyl Cl CH2C02H
C~`3502~
51~ n-butyl Cl CH2 2 3 52~ n-butyl Cl CH ~ N'~
CF3S02- N~ n-propyl Cl a UMR (200 MHz, CDC13) ~ 8.69 (s, lH); 7.82 (S, lH); 7.75 (d, lH, J= 7Hz); 7.59 (d, 2H, J= 1OHZ); 7.55 (d, lH, J= 7HZ); 7.45 (t, lH, J= 7Hz~; 6.87 (d, 2H, J= lOHZ); 5.06 (S, 2H); 3.60 (5, 3H); 3.46 (5, 2H); 2.54 (t, 2H, J= 7HZ); 1.55 (t of t, 2H, J=
7,7Hz); 1.24 ( t of q, 2H, J= 7,7HZ); 0.78 (t, 3H, J= 7HZ).
ExamPle 54 PART A: Preparation of Ethyl n-heptylimidate hydro~hloride To a 601ution of caprylonitrile (30 g, 0.24 mol) in 25 mL of absolute ethanol cooled to 0 wa~ bubbled HCl ga~ (9.6 g, 0.26 mol). After 7 day6 at 0 the vi6cou6 601ution wa6 diluted with 250 mL of anbydrou6 ether and the precipitated product wa6 filtered with 6uction onto a coar6e frit and wa6hed liberally with ether before placing under a vacuum to remove re6idual 601vent. The product wa6 6tored under nitrogen at 0 to yield 22 g (44~) of a-white solid. N~R (200 MHz, DMSO-d6) ~ 4.40 (q, 2H, J= 7Hz): 3.30 (m, 4H): 2.45 (m, 4H): 1.40-0.75 (m, 12H). ~a66. Spec. 172 (M-Cl).
PART B: Preparation of 2-Heptyl-5-(hydroxymethyl)-imidazole In a high-pre66ure (bomb) reactor wa6 placed ethyl n-heptylimidate hydrochloride (22 g, 0.11 mol), 1,3-dihydroxyacetone dimer (9.5 g, 0.053 mol) and liquid ammonia (60 g, 3.5 mol). The reactor wa6 6ealed and heated to 70 for 12 hour6. The crude product (24.7 g) wa~ purified by fla6h chromatography (6ilica gel, 300 g: 10:1 EtOAc/EtOH) to give 12.7 g (61%) of a light yellow 601id: m.p. 82-84. NMR (200 MHz, CDC13/Acetone-d6) ~ 6.75 (6, lH): 4.50 (6, 2H):
4.50-4.25 (br 6, 2H): 2.60 (t, 2H, 8Hz): 1.75-1.60 (m, 2H): 1.40-1.15 (m, 8H): 0.95-0.75 (m, 3H). Ma66 Spec.
196, 167 (M-Et), 149 (M-Et-H20).
- I 3340~2 PART C: Preparation of 4-Chloro-2-heptyl-5-hydroxy-methylimidazole To a solution of 2-heptyl-5-(hydroxymethyl)-imidazole (10.0 g, 51 mmol) in EtOH/1,4-dioxane (1:1:
600 mL) was added N-chloro6uccinimide (7.9 g, 59 mmol). After being 6tirred for 1 hour at room temperature the solvent6 were removed on a rotary evaporator and the 601id re~idue was partitioned between ethyl acetate and vater ~300 mL each). The organic phase was wa6hed with vater (150 mL), dried (MgSO4), filtered and concentrated to afford 12.4 g crude product. Recrystallization (1:1 EtOAc~hexane, 60 mL) gave 5.7 g (45%) of vhite cry6tal6: m.p.
134-140. NMR (200 MHz, CDC13~CD3OD) ~ 4.50 (6, 2H) 4.00-3.80 (br 6, 2H); 2.65 (t, 2H, 5Hz);
1.80-1.60 (m, 2H); 1.40-1.20 (m, 8H); 0.90-0.80 (m, 3H). Ma6s Spec. 230.
PART D: Preparation of 4-Chloro-2-heptyl-5-(hydroxy-methYl)-l-(4-nitrobenzyl~imidazole To a solution of 4-chloro-2-heptyl-5-(hydroxy-methyl)imidazole (5.2 g, 20.7 mmol) in dry DM~ (100 mL) wa6 added anhydrou6 K2CO3 (4.3 g, 31.1 mmol) followed by 4-nitrobenzylbromide (5.4 q, 24.9 mmol). The solu-tion wa6 6tirred 3-5 hour6 at 65-70. The reaction mixture wa6 poured into a separatory funnel containing EtOAc and H2O (300 mL each). The agueou6 phase wa6 extracted with EtOAc (150 mL) and the combined organic phase6 were wa6hed three time6 with H2O (150 mL) before being dried (MgSO4), filtered and concentrated to give 9.0 g brown crude oil. Chromatography (silica gel, 450 g: 1:1 EtOAc/hexane6) gave 1.3 g (17% overall, 35S
of theoretical); m.p. 110-115. NMR (200 MHz, CDC13) ~ 8.20 (d, 2H, 5Hz); 7.20 (d, 2H, 5Hz): 5.35 (s, 2H);
4.45 (~, 2H): 3.10-3.00 (m, lH): 2.50 (t, 2H, 5Hz):
-125 1 3340~2 1.75-1.50 (m, 2H): 1.40-1.10 (m, 8H); 0.90-0.75 (m, 3H). Mass Spec. 365.
PART E: Preparation of 1-(4-Aminobenzyl)-4-chloro-2-heptyl-5-hydroxymethylimidazole To a 601ution of 4-chloro-2-heptyl-S-hydroxy-methyl-1-(4-nitrobenzyl)imidazole (1.00 g, 2.7 mmol) in EtOH (30 mL) and qlacial acetic acid (5 mL) wa6 added iron powder (2.5 g, 44.8 mmol). The mixture was 6tirred while being refluxed for 20 minute6. The 601ution wa6 cooled, the iron wa6 removed by filtra-tion, and the 601ution wa6 partitioned between EtOAc and 20% aq. K2C03 (150 mL each). The organic phase wa6 wa6hed with 6aturated agueou6 NaCl, dried (MgS04), filtered and concentrated to afford 0.8 g yellow-orange oil. Fla6h chromatography (silica gel, 25 q:
EtOAc/hexane6, 1:1) gave 0.74 g (80~) of yellow-orange oil. NMR (200 MHz, CDC13) ~ 6.80-6.60 (ABq, 4H, 7Hz,32Hz): 5.10 (6, 2H): 4.45 (6, 2H): 3.75-3.60 (m, 20 ZH): 2.55 (t, 2H, 5Hz): 1.75-1.65 (m, 2H): 1.30-1.15 (m, 8H); 0.90-0.80 (m, 3H). Ma66 Spec. 335.
PART ~: Preparation of 4-Chloro-2-heptyl-5-hydroxy-methyl-l-t4-((N-trifluoromethane6ulfonyl)-anthranilamido~benzYllimidazole To a 601ution of 1-(4-aminobenzyl)-4-chloro-2-heptyl-5-(hydroxymethyl)imidazole (211 mg, 0.63 mmol) in dry methylene chloride (10 mL) wa6 added anhydrou6 60dium bicarbonate (263 mg, 3.1 mmol) followed by N-(trifluoromethanesUlfOnYl)anthranOYl chloride (180 mg, 0.63 mmol). After 2 hour6 the mixture wa6 filtered, the filtrate was concentrated and the residue was purified by fla~h chromatography (silica gel, 10 g; EtOAc) to provide 298 mg (81%) of pale yellow 601id; m.p. 90-95 (dec.). NMR (200 MHz, -CDC13~CD30D) ~ 7.75-6.80 (m, 8H); 5.10 (6, 2H):
4.gO (s, 2H); 2.50 (t, 2H, 7Hz); 1.75-l.S0 (m, 2H);
1.35-1.15 (m, 8H); 0.95-0.80 (m, 3H). Ma66 Spec - no mass ion observed due to apparent decomposition; 424 ( 2 3 3) Example 55 PART A: Preparation of Ethyl 3-methoxypropylimidate hYdrochloride This compound was prepared according to the procedure de6cribed in Example 54, Part A. Prom 3-methoxypropionitrile (30 g, 0.35 mol) and hydrogen chloride (14.1 g, 0.39 mol) in ethanol (25 mL) there wa6 obtained 37.7 g (64~) white solid. Has~ Spec. 132 lS (N-Cl).
PART B: Preparation of S-Hydroxymethyl-2-(2-methoxyethYl)imidazole This compound wa6 prepared according to the procedure described in Example 54, Part B. From etbyl 3-methoxypropylimidate (36.7 g, 0.22 mol), 1,3-dihyd-roxyacetone dimer (19.7 g, 0.11 mol) and liquid ammonia (90 g, 5.3 mol) there was obtained 14.0 g (41~) of an off-white 601id following chromatography, 25 m.p. 100-107. NMR (200 MHz, DMSO-d6) ~ 6.70 (6, lH); 4.30 (6, 2H): 3.6 (t, 2H, SHz): 3.20 (s, 3H):
2.80 (t, 2H, 5Hz). Mass Spec. 156.
PART C: Preparation of 4-Chloro-5-hydroxymethyl-2-(2-methoxYethyl~imidazole This compound wa~ prepared accordiDg to the procedure described in Example 54, Part C. From 4-hydroxymethyl-2-(2-methoxyethyl)imidazole (13.5 g, 81.7 mmol) and N-chlorosuccinimide (13.8 g, 103 mmol) was obtained 4.8 g (29~) of light yellow solid fol-lowing chromatography (6ilica gel, 500 q: EtOAc); m.p.102-108. NMR (200 MHz, CDC13/CD30D) ~ 4.50 (6, 2H); 3.65 (m, 4H); 3.40 (6, 3H); 2.90 (t, 2H, 5Hz).
Mas6 Spec. 190.
PART D: Preparation of 4-Chloro-5-~ydroxymethyl-2-(2-methoxyethyl)-1-(4-nitrobenzyl)imidazole Thi~ compound wa6 prepared according to the procedure de~cri~ed iD Example 54, Part D. Prom 4-chloro-5-hydroxymethyl-Z-~2-methoxyethyl)imidazole (4.3 g, 22.6 g) was obtained 2.2 9 (30S overall, 60%
of theoretical) of light yellow solid; m.p. 91-95.
NMR (200 MHz, CDC13) ~ 8.15 (d, 2H, 8Rz): 7.20 (d, 2H, 8Hz); 5.45 (8, 2H); 4.45 (6, 2H); 3.60 (t, 2H, 5Hz); 3.20 (6, 3H); 3.15 (6, lH); 2.80 (t, 2H, 5Hz).
Ma66 Spec. 325.
PART E: Preparation of 1-(4-Aminobenzyl)-4-chloro-5-hydroxYmethyl-2-(2-methoxyethyl)imidazole Thi6 compound wa6 prepared according to the procedure de6cribed in Example 54, Part E. Prom 4-chloro-5-hydroxymethyl-2-(2-methoxyethyl)-1-(4-nitrobenzyl)imidazole (2.2 g, 6.75 mmol) and iron powder (6.7 g, 120 mmol) there wa6 obtained 1.6 g (80%) of light yellow 601id; m.p. 164-167. NMR (200 MHz, CDC13/CD30D) ~ 6.80 (d, 2H, 7Hz); 6.65 (d, 2H, 7Hz): 5.15 (6, 2H): 4.45 (6, 2H): 4.30 (~, 3H):
3.60 (t, 2H, 5Hz); 3.25 (6, 3H): 2.8 (t, 2H, 5Hz).
Ma66 Spec. 295.
1 3340q2 PART F: Preparation of l-t4-(2-Carboxybenzamido)-benzyl]-4-chloro-5-hydroxymethyl-2-(2-methoxy-ethyl)imidazole To an acetonitrile 601ution (12 mL) of 1-(4-S aminobenzyl)-4-chloro-5-hydroxymet21yl-2-(2-methoYy-ethyl)imidazole (150 mg, 0.51 mmol) wa6 added an acetonitrile solution (2 ~L) of phthalic anhydride (75 mg, 0.51 mmol). After stirrinq overnight at room temperature a light yellow precipitate wa~ produced.
The mixture was cooled to 0, filtered with ~uction onto a fine fritted funnel and the solid wa6 wa~hed wit~ cold acetonitrile, chloroform and finally ether (2 mL each) to afford 180 mg (80~) of light tan 601id, m.p. 185-186 (dec.). NMR (200 MHz, CDC13/CD30D) ~
8.05-6.95 (m, 8H); 5.30 (s, 2H): 4.50 (6, 2H): 3.60 (t, 2H, 5Hz): 3.25 (6, 3H): 2.8 (t, 2H, 5Hz). Mas6 spec Calcd- for C22H18ClN33 (M 2H2 ) Found: 407.1031.
ExamPle 56 Preparation of 4-Chloro-5-~ydroxymethyl-2-(2-methoxy-ethyl)-l-t4-((N-trifluoromethane~ulfonyl)anthranil-amido)benzYllimidazole Thi6 compound wa~ prepared according to the procedure de6cribed in Example 54, Part F. From 1-(4-aminobenzyl)-4-cbloro-5-hydroxymethyl-2-(2-methoxyethyl)imidazole (200 mg, 0.68 mmol), N-(tri-fluoromethanesulfonyl)anthranoyl chloride (190 mg, 0.68 mmol) and 60dium bicarbonate (280 mg, 3.3 mmol) in acetonitrile (5 mL) wa6 obtained 300 mg (81~) of tan 601id after chromatography (6ilica gel, 20 g:
EtOAc/EtOH, 20:1); m.p. 75-95 (slow dec.) one 6pot by TLC. NMR (200 MHz, CDC13~CD30D) ~ 8.00-6.80 (m, 8H); 5.15 (~, 2H): 4.45 (~, 2H); 3.60 (t, 2H, 5Hz); 3.15 (s, 3H); 2.75 (t, 2H, 5Hz).
1 33409~
The following compound6 li6ted in Table 4 were prepared by the procedure~ de~cribed in Example6 54.
Parts D, E and 54, Part F or 55, Part F.
Table ~
lo a6~ 3 ~x .
No. R ~ MP(-C) 57 ~ ethyl (amorphou6 601id) CF3S02N ~
58 ~ i-propyl (a~orphous 601id)b S9 ~ n-butyl tamorPhou6 601id)C
~ n-pe~tyl (amorphou6 601id)d CF3 02H CH2 (amorphou6 601 id)e 62 ~ ethyl 188-189.5 H02C (free acid) ~- 130 1 334092 Table 4 ( continued) Ex.
No. R R6 MP(C) 63 ~ n-propyl 181.5-183 HO2C (free acid) 64 ~ n-butyl 188.5-189.5 HO2C (Na+salt) ~ n-pentyl 170.5-171.5 66 ~ n-hexyl 171-171.5 67 ~ n-heptyl 181-182 69 ~ ~CH2 ~ CH3O-~-CH2 150-152 71 ~ ~CH2 175 - 177 X.
a NMR ~ 8.05 (d, lH); 7.62 (d, 2H): 7.52 (d, lH); 7.30 (t, lH); 7.17 (m, 3H); 6.93 (m, 2H):
5.13 (s, 2H): 2.61 (quart., 2H); l.lS (t, 3H).
b NMR ~ 8.04 (d, lH); 7.63 (d, 2H); 7.51 (d, lH); 7.2~ (t, lH); 7.13 (m, 3H); 6.89 (m, 2H);
5.14 (~, 2H); 3.11 (~ept., lH); 1.11 (d, 6H).
c NMR ~ 8.05 (d. lH); 7.64 (d, 2H); 7.52 (d, lH); 7.30 (t, lH); 7.17 (m, 3H); 6.92 (m, 2H);
5.15 (6, 2H); 2.66 (t, 2H): 1.53 (quint.. 2H):
1.28 (6ext., 2H): 0.83 (t, 3H).
d NMR ~ 8.07 (d, lH): 7.68 (d, 2H): 7.52 (m, 2H); 7.30 (m, 4H); 6.93 (t, lH); 5.29 (~, 2H);
2.83 (t, 2H); 1.56 (m, 2H); 1.24 (m, 4H); 0.82 (t, 3H).
e NMR ~ 8.03 (d, lH); 7.61 (d, 2H); 7.51 (d, lH); 7.28 (t, lH); 7.10 (m, 3H); 6.91 (t, lH);
6.78 (~, lH); 5.09 (~, 2H); 2.46 (d, 2H); 1.62 (m, 6H); 0.99 (m, 5H).
-ExamPle 72 PART A: Preparation of 5-Hydroxymethyl-2-mercapto-1-(4-nitrobenzYl)imidazole A mixture of 4-nitrobenzylamine hydrochloride (75 g, 0.40 mol), 1,3-dihydroxyacetone dimer (32.1, 0.17 mol) and potassium thiocyanate (51.9 g, 0.53 mol) in n-butanol (250 mL) and glacial acetic acid (40 mL) was 6tirred vigorously at room temperature for 48 hour6.
The mixture wa6 suction filtered and the 601id was washed thrice with water (300 mL) and thrice with ether (300 mL) before beinq dried overnight under vacuum to give 70.9 g (75t) of a yellow tan powder:
m.p. 214-215 (dec.). NMR (200 MHz, DMSO-d6) ~
12.25 (s, lH; ab6ent in D20 sha~e): 8.20 (d, 2H, 15 B~z); 7.40 (d, 2H, 8Hz): 6.90 (6, lH): 5.40 (s, 2H):
5.25 (t, lH, 5Hz: absent in D20 shake): 4.15 (d, 2H, 5Hz: s in D20 6hake). Mas6 Spec. 265.
PART B: Preparation of 5-Hydroxymethyl-2-methylthio-1-(4-nitrobenzyl~imidazole An ethanolic solution of sodium ethoxide was prepared by the gradual addition of 60dium hydride (0.70 g of 60~ NaH in mineral oil, 17.6 mmol) to absolute ethanol (150 mL). To thi6 5-hydroxymethyl-25 2-mercapto-1-(4-nitrobenzyl)imidazole (3.9 g, 14.7 mmol) wa~ added and after being stirred 5-10 minutes, iodomethane (2.5 g, 1.1 mL, 17.6 mmol) was added.
After being stirred 3 hours at room temperature, the mixture was concentrated on a rotary evaporator and the residue was partitioned between ethyl acetate (500 mL) and water (250 mL). The aqueous phase wa6 further extracted with ethyl acetate (250 mL) and the combined organic phases were washed with water (150 mL), saturated aqueous sodium chloride (150 mL), dried (MgS04), filtered and concentrated to leave 4.1 g of 133 ~ 3340q 2 yellow-brown 601id. Recry~tallization from ethyl acetate gave 2.6 g (64%) of light yellow-broWn powder;
m.p. 160-162. NMR (200 MHz, DNSO-d6) ~ 8.20 (d, 2H, 7Hz); 7.30 (d, 2H, 7Hz); 6.95 (6, lH); 5.40 (6, 2H); 5.20 (t, lH, 5Hz; absent in D2O 6ha~e): 4.40 (d, 3H, 5Hz; 6 in D20 6hake); 3.40 (6, 2H;
monohydrate: ~ 3.5 in D20): 2.45 (6, 3H).
Mas6 Spec. 279.
0 PART C: Preparation of 1-(4-Aminobenzyl)-5-hydroxy-methyl-2-tmethYlthio)imidazole Thi6 compound was prepared according to the procedure described in Example 54, Part E, from 5-hydroxymethyl-2-methylthio-1-(4-nitrobenzyl)imid-azole (21 g, 75.2 mmol) and iron powder (75 g, 1.3mol) there was obtained 13.5 g (72%) of a yellow hygroscopic 601id. NMR (200 MHz, CDC13) ~ 6.90 (6, lH); 6.85-6.45 (g, 4H, SHz,51Hz): 5.10 (6, 2H);
4.40 (6, 2H): 2.40 (6, 3H). Mas6 Spec. 249.
PART D: Preparation of 1-[4-(2-Carboxybenzamido)-benzyl]-5-hydroxymethyl-2-(methylthio)-imidazole This compound was prepared according to the procedure de6cribed in Example 55, Part F, though in this case the reaction was run in chloroform and the filtered product wa6 washed with chloroform and ether.
From 1-(4-aminobenzyl)-5-hydroxymethyl-2-(methylthio)-imidazole (323 mg, 1.3 mmol) and phthalic anhydride (192 mg, 1.3 mmol) there wa6 obtained 488 mg (95%) of the title compound a6 a yellow powder: m.p. 115-118 (dec.). NMR (200 MHz, CDC13/DMSO-d6) ~ 9.80 (6, lH): 8.00-6.85 (m, 9H): 5.20 (6, 2H): 4.40 (6, 2H);
2.50 (s, 3H). Mass Spec. 379 (M-H2O).
Example 73 Preparation of l-t4-(2-Carboxybenzamido)benzyl-5-hydroxymethyl-2-methoxYimidazole By repeating Example 72, Part6 C and D, but 6ubstituting 5-hydroxymethyl-2-methoxy-1-(4-nitro-benzyl)imidazole a6 6tarting ~aterial in Part C, the compound l-t4-(2-carboxybenzamido)benzyll-5-hydroxy-methyl-2-methoxyimidazole can be prepared.
ExamPle 74 PART A: Preparation of tran6-2-(Trifluoromethane-6ulfonamido)cYclohexanecarbo~ylic acid Ethyl trans-2-(trifluoromethane6ulfonamido)cyclo-hexanecarboxylate wa6 ~ynthe~ized from ethyl tran6-2-aminocyclohexanecarboxylate lE. J. Moriconi and P. H.Mazzocchi, J. Orq. Chem., 31, 1372 (1966)] by the procedure de6cribed in Example 21. The crude product (2.59 g, 8.55 mmol, 1 eq) wa~ then hydrolyzed by refluxing in 1.00N NaOH (26.5 mL, 26.5 mmol, 3.1 eq) overnight under N2. Water (100 mL) wa6 then added and the pH adjusted to 3 u6ing 1_ HCl. The aqueous wa6 extracted with ethyl acetate (3 x 100 mL), the organic layer6 dried (MgS04) and concentrated to yield a cry6talline white 601id which wa~ recry6tal-lized from n-butyl chloride. Obtained 1.71 g of product: m.p. 114.5~ .5. NMR (200 MHz, DMSO-d6) 12.47 (bs, lH): 9.52 (bs, lH): 2.35 (d of d of d, lH, J= 10,10,4Hz): 2.10-1.13 (m, 9H). Anal. Calcd.
for C8H12~3NO4S: C, 34.91: H, 4.39: N, 5.09.
Pound, C, 34.73: H, 4.22; N, 5.04.
- 1 3340~2 PART B: Preparation of Methyl 2-butyl-4-chloro-1-t4-(trans-2-(trifluoromethane6ulfonamido)cyclo-hexanecarboxamido)benzyl]imidazole-5-acetate and methyl 2-butyl-4-chloro-1-t4-(cis-2-(tri-fluoromethane6ulfonamido)cyclohexanecarbox-amido)benzyl~imidazole-5-acetate trans-2-(Trifluoromethanesulfonamido~cyclohexane-carboxylic acid (500 mg, 1.82 mmol, 1 eq) and thionyl chloride (2.30 mL, 31.5 mmol, 17.3 eq) were mixed and refluxed for 2 hours. The exces6 thionyl chloride wa~
removed in vacuo and the residue suspended in toluene.
The toluene wa6 removed by rotary evaporation and the procedure repeated to remove trace6 of thionyl chlor-ide. Final rotary evaporation yielded 460 mg of white cry6talline acid chloride product which wa6 u6ed with-out furtber purification (IR 1789 cm 1).
Methyl 2-butyl-4-chloro-1-(4-aminobenzyl)-imidazole-5-acetate (530 mg, 1.57 mmol, 1 eq), tran6-2-(trifluoromethanesulfonamido)cyclohexanoyl chloride (460 mg, 1.57 mmol, 1 eq) and 60dium bicarbonate (400 mg, 4.70 mmol, 3 eq) were mixed and 6tirred in chloro-form (20 mL) overnight. Water (100 mL) wa6 then added, and the pH adjusted to 4 with lN HCl. The aqueou~ was extracted with methylene chloride (3 x 100 mL) and the organic layer6 dried and concentrated. Gradient flash chromatography of the residue in 60:40 hexane/ethyl acetate to 100% ethyl acetate over 6ilica gel yielded two isomer6: both of which were i601ated a~ gla66e~.
The faster eluting product being the minor Ci8 i60mer (170 mg) while the 610wer being the major trans isomer (520 mg).
_ 136 1 ~340~2 trans-Isomer; NMR (200 MHz, CDC13) ~ 8.18 (s, lH): 7.42 (d, 2H, J= lOHz); 6.84 (d, 2H, J= lOHz);
6.47 (bd, lH, J= 8Hz): 5.07 (s, 2H); 3.72 (m, lH):
3.57 (s, 3H); 3.47 (s, 2H); 2.53 (t, 2H, 7Hz):
2.24-1.12 (m, 13Hz): 0.82 (t, 3H, J= 7Hz). Anal.
Calcd. for C25H32C1~3N4O5S: C, 50.63 H, 5.q4 N, 9.45. Found: C, 50.64: H, 5.44: N, 9.16. Mass Calcd. for C25H32ClF3N4O5S: 592.173q. Pound:
592.1731.
cis-Isomer: NMR (200 MHz, CDC13) ~ 7.94 (s, lH): 7.42 (d, 2H, J= lOHz): 6.88 (d, 2H, J= lOHz):
6.52 (bd, 2H, J= 8Hz): 5.11 (s, 2H): 3.75 (m, lH):
3.63 (8, 3H): 3.48 (s, 2H): 2.56 (t, 2H, 7Hz):
2.29-1.25 (m, 13H): 0.86 (t, 3H, J~ 7Hz). Anal.
25 32 3 4 5S: C, 50.63: H, 5.44.
Found: C, 49.87: H, 5.65. Mass Calcd. for C25H32ClF3N4O5S: 592.1734. ~ound: 592.1689.
ExamPle 75 PART A: PreParation of 2-Butyl-4,5-dicyanoimidazole Ethyl pentanimidate hydrochloride (42.66 g, 257.8 mmol, 1 eq), diaminomaleonitrile (27.90 g, 258.1 mmol, 1 eq) and pyridine (400 mL) were mixed and refluxed for 48 hours under N2. The solvent was removed by rotary evaporation.
The residue wa6 taken up in ethyl acetate and filtered through a pad (3" Y 4") of ~lorisil*. The solvent was removed in vacuo and the residue fla6h chromatographed in 60:40 ~exane/ethyl acetate over silica gel to give 16.59 g of a yellow solid w~ich was used in the following step without further purifica-tion. An analytical sample was prepared by recrystal-li~ing the crude product (3.03 g) from ether/~exane to give 1.55 g of yellow crystals; m.p. 108.0-109Ø
* trade mark .~ .
-NMR (200 MHz, CDC13) ~ 2.86 (t, 2H, J= 7Hz): 1.77 (t of t, 2H, J= 7,7Hz); 1.41 (t of q, 2H, J= 7,7Hz):
0.98 (t, 3H, J= 7Hz). Anal. Calcd. for CgHloN4:
C, 62.05; H, 5.79: N, 32.16. Pound: c, 62.28: H, 5.81; N, 32.22. Mass ~pectrum ~hows M-H pea~. Ma~s Calcd. for CgHloN4-H: 173.0827. ~ound: 173.0785.
PART B: Preparation of 2-Butyl-4,5-dicyano-1-(4-nitrobenzYl)imidazole 2-n-Butyl-4,5-dicyano-1-(4-nitrobenzyl)imidazole was prepared from 2-n-butyl-4,5-dicyanoimidazole by the procedure in Example 1, Part A u6ing q-nitrobenzyl bromide as the alkylating agent. The product wa6 obtained as an oil. NMR ~200 MHz, CDC13) ~ 8.29 (d, 2H, J= lOHz): 7.29 (d, 2H, J. lOHz): 5.36 (6, 2H);
2.67 (t, 2H, Jz 7Hz): 1.70 (t of t, 2H, J. 7,7Hz):
1.36 (t of q, 2H, J= 7,7Hz); 0.86 (t, 3H, J= 7Hz).
~ass Calcd. for C16H15N502 309.1211.
PART C: Preparation of 1-(4-Aminobenzyl)-2-butyl-4,5-dicyanoimidazole A mixture of 2-butyl-4,5-dicyano-1-(4-nitrobenz-yl)imidazole (2.00 g, 6.5 mmol, 1 eq), tin dichloride dihydrate (7.30 g, 32.3 mmol, 5 eq) and ethanol (13 mL) wa~ 6tirred and heated at 70 for 50 minute~. The reaction wa6 terminated by pouring the mixture onto ice and adjusting the pH to 8 with 6aturated aqueous NaHCO3. The aqueou6 mixture wa6 extracted with ethyl acetate (3 x 100 mL) and the organic layer~ were dried (MgS04) and concentrated to give a thic~ amber oil, Thi6 oil was flash chromatographed over 6ilica qel in 75:25 to 70:30 hexane/ethyl acetate yielding 330 mg of yellow crystals; m.p. 99.0-103.5. NMR (200 MHz, CDC13) ~ 6.97 (d, 2H, J= lOHz); 6.68 (d, 2H, J=
lOHz); 5.10 (s, 2H); 2.69 (t, 2H, J= 7Hz); 1.72 (t of t, 2H, J= 7,7Hz); 1.38 ( t of q, 2H, J= 7,7Hz); 0.91 (t, 3H, J= 7Hz). Mas6 Calcd. for C16H17N5:
279.1483. Found: 279.1489.
PART D: Preparation of 2-Butyl-4,5-dicyano-1-14-((N-trifluoromethane6ulfonyl)anthranilamido)-benzyl~imidazole The title compound was prepared by the procedure described in Example 30 starting with 1-(4-aminobenz-yl)-2-butyl-4,5-dicyanoimidazole and N-(trifluoro-methanesulfonyl)anthranilic acid chloride. NMR (200 MHz, CDC13 ~ DMS0-d6) ~ 7.98 (d, lH, J= 7Hz): 7.32 (d, 2H, J= 7Hz): 7.62 (d, lH, J= 7Hz); 7.47 (d of d, lH, J= 7,7Hz): 7.24 (d of d, lH, Js 7,7Hz): 7.15 (d, 2, J=
7,7Hz): 5.32 (6, 2H): 2.75 (t, 2H, J= 7Hz): 1.70 (t of t, 2H, J= 7,7Hz): 1.37 ( t of g, 2H, J= 7,7Hz): 0.92 (t, 3H, J= 7Hz). ~ass Calcd. for C24H21F3N603S:
503.1348. Found: 530.1343.
ExamPle 76 PART A: ~reparation of Metbyl l-t4-(N-benzylamino)-benzYl~-2-butYl-4-chloroimidazole-5-acetate A mixture of methyl 1-(4-aminobenzyl)-2-butyl-4-chloroimidazole-5-acetate (1.00 g, 3.0 mmol, 1 eg), benzaldehyde (0.30 mL, 3.0 mmol, 1 eq), 4A powdered molecular 6ieves (enough to make a slurry) and 40 mL
THP was 6tirred overnight. The next day, more benz-aldehyde (0.2 mL) and acidic A1203 (activity 1, lg) were added and t~e 61urry stirred anotber 24 ~ours.
The solids were filtered and the solvent from the filtrate removed in vacuo. The re6idue was dis~olved in methanol (10 mL) and sodium cyanoborohydride was added (0.19 9, 3.0 mmol, 1 eq). The mixture was stirred for 24 hours, after which the 601vent was removed in vacuo to yield a green oil which was flash chromatographed over silica gel in 70:30 hexane/ethyl acetate to give 740 mg of product as an oil. NMR (200 MHz, CDC13) ~ 7.42 - 7.24 (m, 5~): 6.74 td, 2H, J=
7Hz): 6.56 (d, 2H, J= 7Hz): 4.98 (s, 2H): 4.31 (6, 2H): 3.61 (s, 3H): 3.48 ts. 2H) 2.60 (t, 2H, J= 7Hz):
1.67 (t of t, 2~, J= 7,7Hz): 1.35 (t of g, 2H, Js 7,7Hz): 0.89 (t, 3H, Js 7Hz). Ma66 Calcd. for C24H28C1~302: 425.1868. Found: 425.1853.
PART B: Preparation of Methyl 2-butyl-1-t4-(N-benzyl-N-(2-(trifluoromethanesulfonamido)benzoyl)-amino)benzYll-4-chloroimidazole-5-acetate The title compound was prepared from the compound of Part A by the procedure described in Example 30.
NMR (200 MHz, CDC13) ~ 7.59 (d, lH, Js lOHz):
7.33-7.16 (m, 6H): 6.89 (d, 2H, Js lOHz): 6.76 (d, 2H, J= lOHz); 6.93-6.70 (m, 2H): 5.12 (6, 2H); 5.02 (6, 2H); 3.55 (s, 3H); 3.39 (6, 2H); 2.47 (t, 2H, J= 7Hz);
1.64 (t of t, 2H, J= 7,7Hz); 1.30 (t of q, 2H, J=
7,7Hz); 0.88 (t, 3H, J= 7~z). Anal. Calcd. for C32H32ClF3N405S: C, 56.76; H, 4.76; N, 8.27.
Found: C, 56.64; H, 4.90; N, 7.98.
Example 77 PART A: Preparation of 2-n-Butyl-4-chloro-5-methoxy-methY~ lN-methYl-4-aminobenzyl~imidazole 1-(4-Aminobenzyl)-2-n-butyl-4-chloro-5-(methoxy-methyl)imidazole (10.94 g) and ethyl formate (150 mL) were mixed and refluxed overnight. The exces6 ethyl formate was removed in vacuo and another 150 mL added and the mixture was refluxed overnight again. The excess ethyl formate was removed in vacuo and the residue flash chromatographed over silica gel in 1:1 hexane/ethyl acetate to yield 9.52 g of a golden oil which 610wly cry~tallized after 6everal days. Thi6 oil (9.40 g, 28 mmol, 1 eq) was dis601ved in TH~ and to it LAH (lM in THF, 84.0 mL, 84 mmol, 3 eq) was slowly added via syringe under N2. After 6tirring for 1 h, the mixture was worked up a~ described in Pie6er and Fieser, V.l pg. 584 (Steinhardt procedure) to yield 8.47 g of an orange oil. NMR (200 MHz, CDC13) ~ 6.84 (d, 2H, J= lOHz); 6.55 (d, 2H, J.
lOHz); 5.02 (6, 2H): 4.26 (s, 2H); 3.27 (8, 3H); 2.81 (s, 3H); 2.58 (t, 2H, J= 7Hz); 1.67 (t of t, 2H, J=
7,7Hz); 1.35 (t of q, 2H, J~ 7,7Hz); 0.87 (t, 3H, J=7Hz). Anal. Calcd. for C17H24ClN30: C, 63.44;
H, 7.52; N, 13.06. Found: C, 63.60; H, 7.61; N, 12.86.
PART B: Preparation of 2-n-Butyl-4-chloro-5-methoxy-methyl-l-t4-(N-methyl-2-carboxy-3,6-dichloro-benzamid)benzyllimidazole 2-n-Butyl-4-chloro-5-methoxymethyl-1-tN-metbyl-4-aminobenzyl~imidazole (2.00 g, 6.2 mmol, 1 eq) and 3,6-dichlorophthalic anhydride (1.35 g, 6.2 mmol, 1 eq) were reacted by the procedure described in Example 2, Part D to give 2.37 g of a white powder; m.p. 120.0-123.5. The NMR 6hows a 7:2 mixture of conformers in DMS0-d6. NMR (200 MHz, DMS0-d6) ~ (major conformer only) 14.25 (m, lH): 7.76-6.85 (m, 6H); 5.09 (s, 2H); 4.18 (s, 2H); 3.06 (s, 3H); 2.37 (t, 2H, J=
7Hz); 1.38 (t of t, 2H, J= 7,7Hz); 1.21 (t of q, 2H, J= 7,7Hz); 0.77 (t, 3H, J= 7Hz). Anal. Calcd. for C25H26C13N304: C, 55.72; H, 4.86; Cl, 19.74, ~ound: C, 55.48; H, 4.88; Cl, 19.77.
Example 78 PART A: Preparation of 2-n-Butyl-1-(4-carbomethoxy-benzyl)-4-chloro-5-(methoxymethYl)imidazole) 2-Butyl-4-chloro-S-hydroxymethyl-1-(4-carboxy-benzyl)imidazole (17.6 g), methanol (500 mL) and conc.sulfuric acid (50 mL) were mixed and refluxed overnight. Pota6sium carbonate (100 g) was then carefully added to the 601ution which was cooled over ice. The reaction mixture wa6 then stirred for 2.5 hours. The solvent was removed in vacuo and the residue di6~01Yed in water (1 L). Thi6 aqueous mixture wa6 extracted with ethyl acetate (3 s 400 mL). The organic layer~ were combined, dried (NgS04) and t~e 601vent removed in vacuo to yield 15.2 g of an oil. NMR (200 MHz, DMSO-d6) ~ 8.46 (d, 2H, J= 9Hz); 7.68 (d, 2H, J= 9Hz): 5.82 (s, 2H);
4.80 (6, 2H): 4.37 (6, 3H); 3.66 (6, 3H); 3.02 (t, 2H, J= 7Hz); 2.01 (t of t, 2H, J= 7,7Hz); 1.77 (t of q, 2H, J= 7,7Hz); 1.33 (t, 3H, J= 7Hz). Anal. Calcd. for C18H23ClN203: C, 61.62; H, 6.61 N, 7.99.
Found: C, 61.79; H, 6.78; N, 7.82.
PART B: Preparation of 2-n-Lutyl-1-(4-carboxybenzyl)-4-chloro-5-(methoxymethYl)imidazole 2-n-Butyl-1-(4-carbomethoxybenzyl)-4-chloro-5-(methoxymethyl)imidazole (15.2 g, 43.3 mmol, 1 eq), 0.5 N KOH in methanol (130 mL, 65.0 mmol, 1.5 eq), water (10 mL) and methanol (50 mL) were mixed and refluxed for 4 hour6. The 601vent wa6 removed in vacuo and the residue di6601ved in water (300 mL).
The pH was adju~ted to 4 with conc. HCl and this aqueous mixture extracted with ethyl acetate (3 x 300 mL). The organic layer~ were combined, dried (MgS04), the solved removed in vacuo and the crude residue recrystallized from hexane/butyl chloride to 1 3~4092 yield 9.6 g of white solid; m.p. 126.5-127.5. NMR
(200 MHz, DMSO-d6) ~ 12.95 (bs, lH); 7.93 (d, 2H, J= 9Hz): 7.16 (d, 2H, J= 9Hz): 5.30 (s, 2H): 4.31 (s, 2H); 3.19 (s, 3H); 2.50 (t, 2H, J= 7Hz); 1.49 (t of t, 2H, J= 7,7Hz); 1.24 (t of q, 2H, J~ 7,7Hz): 0.80 (t, 3H, J= 7Hz). Anal. Calcd. for C17H21ClN203:
C, 60.62; H, 6.29; N, 8.32. ~ound: C, 60.89; H, 6.10; N, 8.03.
0 PART C: Preparation of 2-n-Butyl-l-t4-(N-(2-carboxy-phenyl)carboxamido)benzyl]-4-chloro-5-methoxymethyl~imidazole 2-n-Butyl-1-(4-carboxybenzyl)-4-chloro-5-(methoxymethyl)imidazole (6.00 g, 17.8 ~mol, 1 eq), thionyl chloride (13.0 mL, 178 ~mol, 10 eq) and chloroform (100 mL) were mixed and refluxed for 6 h.
The solvent wa~ removed in vacuo, and the re~-idue dis601ved in toluene. The solvent was removed on the rotary evaporator and the evaporation from toluene repeated to remove all of the thionyl chloride. This yielded 6.0 g of acid chloride a~ an amber gum. lR
1776, 1745 cm . Anthranilic acid (0.737 g, 5.36 mmol, 1 eq) was di~solved in 1.000 N NaOH (10.75 mL, 10.7 mmol, 2 eq) and water (100 mL) and cooled over ice. The aforementioned acid chloride (1.91 g, 5.36 mmol, 1 eq) dissolved in THF (50 mL) was ~lowly added via a dropping funnel to the 6tirred and cooled antbranilic acid solution. The following day, more anthranilic acid (74 mg, 0.536 mmol, 0.1 eq) wa~ added to bring the reaction to completion. After 1.5 h, the ~olution was acidified to pH=5 with lN HCl and extracted with ethyl acetate (1 x lOOmL). The ethyl acetate layer was then was~ed with water (3 x 50 mL), and brine (1 x 50 mL), dried (MgS04) and the 601vent removed in vacuo to yield 2.28 9 of a brown glass.
-This glass was dissolved in a minimum amount of ethyl acetate and dicyclohexylamine ("DCHA", 1 eq) was added thereto. The salt did not crystallize and therefore was flash chromatographed over silica gel starting in 100~ ethyl acetate and finishing in 1:1 ethyl acetate~-isopropanol to yield 1.44 g of an oil. This oil was dissolved in ethyl acetate (100 mL) and a minimum of methanol, and washed with lN HCl (2x50mL). The ethyl acetate layer was dried (MgS04) and the solvent removed in vacuo to yield 0.52 g of an amber oil. NMR
(200 MHz, CDC13) ~ 12.53 (s, lH): 8.91 (d, lH, J=
8Hz); 8.23 (d, lH, J= 7Hz): 8.08 (d, 3H, J= 7Hz): 7.62 (t, lH, J= 6Hz): 7.11 (t, 2H, J= 7Hz): 5.30 (6, 2H):
4.30 (s, 2H): 3.30 (s, 3H); 2.72 (t, 2H, J= 7Hz): 1.72 (t of t, 2H, J= 7,7Hz): 1.31 (t of q, 2H, J= 7,7Hz):
0.83 (t, 3H, J= 7Hz). Anal. Calcd. for 25 25 3 4 (H20)1.5: C, 59.81: H, 5.85: Cl 7 36 Found: C, 59.78; H, 6.38; Cl, 7.51.
Examples 79-84 in Table 5 were made or could be made by procedures described in Example 78 and by methods familiar to one skilled in the art.
Table S
N ~
a6 ~N~ 8 Ex.
No. R R R R MP(C) 79 n-butyl Cl CH20CH3 N-N~ (,300) -u - ~N,N
H H
-- T~hle 5 (continued) 1 334092 E~ R6 Rl R8 ~ MP (C) 80 n-butyl Cl CH20CH3 _~ (glass)b HO,,J~
81 n-butyl Cl CH2OCH3 ~ (white solid)C
N N~J~
82 n-butyl Cl CH20CH3 H 149-152 ,N~,COOH
.. ~
Lffomer 83 n-butyl Cl CH20CH3t-~ 134.5-136 _ N~l~
COOH
L-isorrler 84 n-butyl Cl CH2OCH3 ~H Cl --N~
HO~,~J
o Cl a NMR (200 MHz, DMSO-d6) ~ 8.01 (d, 2H, J=
7Hz); 7.17 (d, 2H, J= 7Hz); 5.31 (s, 2H);
4.27 (s, 2H); 3.18 (s, 3H); 2.50 (t, 2H, J=
7Hz); 1.50 (t of t, 2H, J= 7,7Hz); 1.21 (t of q, 2H, J= 7,7Hz); 0.~0 (t, 3H, J= 7Hz).
b NMR (200 MHz, CDCl3` ~ 11.52 (s, lH) 8.55 (d, lH, J= 7 Hz)j 8.0 (d, 2H, J= 7Hz) 7.41 (t, lH, J= 7Hz); 7.14 (d, 2H, J= 7Hz); 7.04 (d, lH, J= 7Hz); 5.30 (s, 2H); 4.25 (s, 2H);
3.30 (s, 3H); 2.73 (t, 2H, J= 7Hz); 2.60 (s, 3H); 1.68 (t of t (br), 2H); 1.29 (t of q, 2H, J= 7,7Hz); 0.81 (t, 3H, J= 7Hz).
c NMR (200 MHz, CDCl3) ~ 12.05 (s, lH);
8.88 (d, lH, J= 7Hz); 8.23 (d, 2H, J= 8Hz);
8.11 (d, lH, J= 7Hz); 7.51 (t, lH, J= 7Hz);
7.25-7.11 (m, 3H); 5.29 (s, 2H); 4.31 (s, 2H); 3.29 (s, 3H); 2.62 (t, 2H, J= 7Hz); 1.63 (t of t, 2H, J= 7,7Hz); 1.26 (t of q, 2H
J=7,7Hz); 0.75 (t, 3H, J= 7Hz) IR; 1621,753 cm~l ExamPle 85 1 3 3 4 0 9 ~
PART A: Preparation of Methyl 4'-methylbiphenyl-3-carboxYlate To a stirred solution of 25.2 g of methyl 3-iodobenzoate and 21.0 g of 4-iodotoluene at 180-190 under nitrogen was added 30.3 g of copper powder portionwise over 1 hour. When approximately one-third of the copper had been added, the reaction initiated and the temperature increased spontaneously to 2400. The mixture was allowed to cool to 210, then was held at 210 during the addition of the remaining copper and for an additional hour. The mixture was allowed to cool to room temperature and was filtered employing benzene as solvent; the resulting filtrate was concentrated in vacuum to provide the crude product. Cplumn chromatography on silica gel (elution = 50-100% benzene/hexane) followed by distillation furnished 7.60 g of methyl 4' -methylbiphenyl-3-carboxylate [bp: 114-115C (0.025 torr)] as a colorless oil:
NMR (200 MHz, CDC13): ~ 8.27 (br S, lH): 7.99 (d, lH): 7.77 (d, lH): 7.50 (t, lH): 7.39 (A2B2, 4H): 3.94 (s, 3H): 2.41 (s, 3H).
The following methylbiphenyl starting materials were prepared employing the above procedure.
NMR (200 MHz, CDCl3) C02Me a) A ~ ~ 7.78 (d, lH): 7.46 CH~ (d, lH): 7.35 (t, 2H):
~__J~--J 7.19 (s, 4H): 3.64 (s, 3H): 2.37 (s, 3H) 2 ~ 7.80 (d of d, lH):
~ ~ 7.57 (t of d, lH): 7.41 b)CH~ ~ ~ (m, 2H) 7 19 (s, 4H):
~l `- 1 33409~
Alternatively methyl 4'-methylbiphenyl-2-car-boxylate (compound a) and tert-butyl 4'-methylbiphenyl-2-carboxylate can be prepared by chemistry described by A. Meyers via the following five-step procedure.
Step 1: Preparation of 2-Methoxybenzoyl chloride ~ o 30 g of Z-ani6ic acid in 500 mL of round-bottom flas~ was added dropwise 50 mL of thionyl chloride. After all of the thionyl cbloride was added the reaction mixture was stirred at room temperature for 18 hour6. Excess thionyl chloride was tben distilled off by water aspirator and the remaining liquid was vacuum di6tilled (82~0.7 mm Hg). Desired 2-methoxybenzoyl chloride wa~ obtained a6 a colorless liquid, 32 g.
Step 2: Preparation of 4,4-Dimethyl-2-(2-methoxy-phenyl)oxazoline 20 g of 2-Amino-2-methyl-1-propanol was dissolved in 100 mL of methylene chloride and the mixture wa6 cooled with ice. Meanwhile, 17 g of 2-methoxybenzoyl chloride prepared from Step 1 was placed in a dropping funnel, diluted with 50 mL of methylene chloride and added dropwise. After the addition of the acid chloride, the cooling ice bath was removed and the reaction mixture was stirred at room temperature for 2 hours.
The reaction mixture was concentrated to remove the solvent and the solids obtained were triturated with water, collected by filtration and washed with water. Thus obtained 601ids were dried in vacuo to give a colorless light solid, 20.5 g.
The solid was placed in 200 mL of round-bottom flask and 22 mL of thionyl chloride was added slowly to the solid without any ~olvent. At the beginning of -1 3~4092 the addition the reaction was vigorou6 but wa6 control-lable. After the addition of thionyl chloride wa6 complete, the yellow reaction mixture wa6 6tirred at room temperature for 1 hour. The reaction mixture wa6 poured into 200 mL of ether and the re6ulting 601id6 were collected and wa6hed with ether. The solid6 were di6601ved in 100 mL of water and t~e pH of the 601ution wa6 adju6ted to 10 by adding lN NaOH. The aqueou6 601ution wa6 extracted into ether 3 time6.
The combined ether extracts were dried (Na2S04) and concentrated to give the de6ired product a6 a white 601id, 18 g, m.p. 70-72.
Step 3: Preparation of 2-(4'-Methylbiphenyl-2-yl)-4,4-dimethYloxazoline 4-Methylphenyl Grignard reagent wa6 prepared from 2.5 g of magne~ium and 13 mL of 4-bromotoluene in 200 mL of anhydrou6 THF. The Grignard reagent wa6 added to 10 g of the product from Step 2 in 100 mL of anhydrou6 TH~ and the reaction mixture wa6 6tirred at room temperature for 2 hour6. The reaction mixture wa6 concentrated and the re6idue wa6 treated with 200 mL of 6aturated NH4C1 601ution and the mixture wa6 6tirred at room temperature for 30 minute6. The aqueou6 601ution wa6 then extracted with ethyl acetate. The crude product obtained upon concentration of the ethyl acetate extract6 were purified by fla6h column chromatography (6ilica gel, hexane:ethyl acetate=2:1) to give the de6ired compound a6 a colorle66 liquid, 11.8 g.
Step 4: Preparation of 4'-Methylbiphenyl-2-carboxylic acid A mixture of 10 g of the product from Step 3 and 200 mL of 4.5 N HCl was refluxed for 12 hour6. During this period of time the de6ired compound was isolated as a brownish oil floating on the surface of the reaction medium. The reaction mixture was cooled to room temperature. The product which was oily initially began to solidify upon cooling. The product was extracted with ethyl ether. Upon concentration of the ether extract the de6ired product was obtained a6 a colorless 601id, 7 g, m.p. 140-142.
0 Step 5: Esterification of 4'-methylbiphenyl-2-carboxYlic acid Preparation of methyl 4'-methylbiphenyl-2-carboxylate To 100 mL of methanol was added dropwise 5 mL of acetyl chloride with ice cooling. After ~tirring the mixture for 15 minute6, 5 g of the acid from Step 4 was added at once and the mixture was refluxed for 4 hour6. The reaction mixture was concentrated to remove the ~olvent and the desired methyl e6ter was obtained as a thick liquid, 5 g.
Preparation of tert-butyl 4~-methylbiphenyl-2-carboxylate To a 601ution of 42.4 g of 4'-methylbiphenyl-2-carboxylic acid in 200 mL of methylene chloride at 0was added dropwi6e 20 mL of oxalyl chloride. The reaction wa6 allowed to warm to 25 and then was stirred at 25 for 3 hours. The 601vent was removed in vacuo. The residue wa6 di6601ved in benzene, and the benzene then removed in vacuo to provide 46.1 g of crude acid chloride.
The acid chloride prepared above wa~ di~solved in 600 mL of tetrahydrofuran. To this solution at 0 was added 26.0 g of potassium t-butoxide portionwise -149 1 3~4092 such that the reaction temperature did not exceed 15-20C. The resulting mixture was then allowed to stir at 25C for 1 hour. The reaction mixture was poured into water, and the resulting emulsion was extracte~ with diethyl ether. The combined organic phases were washed with b~ine, dried over anhydrou~
sodium sulfate, filtered, and concentrated.
Distillation provided 49.5 g of tert-butyl 4'-methyl-biphenyl-2-carboxylate (bp 115-120/O.OS torr). NMR
(200 MHz, CDC13): ~ 7.73 (d of d, lH), 7.46-7.27 (m, 3H); 7.18 (s, 4H): 2.40 (s, 3H): 1.30 (s, 9H).
PART B: Preparation of Methyl 4'-bromomethylbiphenyl-3-carboxylate A solution of 7.31 g of Methyl 4'-methylbiphenyl-3-carboxylate, 5.75 g of N-bromosuccinimide, 0.125 g of azo(bisisobutyronitrile), and S00 mL of carbon tetrachloride was refluxed for 3 hours. After cooling to room temperature the resulting suspension was filtered and then concentrated in vacuo to provide 9.90 g of crude methyl 4l-bromomethylbiphenyl-3-carboxylate which was used in a subsequent reaction without further purification; ~MR (200 MHz, CDC13):
~ 8.28 (s, lH); 8.05 (d, lH); 7.79 (d, lH);
7.67-7.48 (m, SH); 4.55 (s, 2H); 3.98 (s, 3H).
The following bromomethylbiphenyl intermediates were prepared employing the above procedure.
CD~ NMR (200 MHz, CDC13) a) Er ~ ~ 7.82 (d, lH);
7.59-7.23 (m, 7H); 4.52 (s, 2H); 3.62 (s, 3H) 150 1 3340~2 b) y ~ 7.86 (d of d, lH):
~ 7.62 (t of d, lH);
2r 7.53-7.21 (m, 6H); 4.52 (s, 2H) C02C ( CH3 ) 3 c) ~ ~ ~ 7.79 (d, lH);
7.56-7.24 (m, 7H); 4.51 ~r (s, 2H); 1.25 (s, 9H).
PART C: Preparation of l-t(3'-Carbomethoxybiphenyl-4-yl)methyl]-2-butyl-4-chloro-5-hydroxymethyl-imidazole To a suspension of 1.43 g of sodium methoxide in 20 mL of dimethylformamide at 25 was added a 601ution of 5.00 g of 2-butyl-4(5)-chloro-5(4)-hydroxymethyl imidazole in 15 mL of DMF. The resulting mixture was stirred at 25 for 0.25 hours, and then to this mix-ture was added dropwise a solution of 9.90 g of methyl g'-bromomethylbiphenyl-3-carboxylate in 15 mL of DMF.
Finally, the reaction mixture was stirred at 40 for 4 hours. After cooling to 25, the solvent was removed in vacuo. The residue was dissolved in ethyl acetate, and this solution was washed with water and brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product contains two regioisomers, the faster moving one by TLC being the more potent isomer. Column chromatography on silica gel (elution:10-25% ethyl acetate/benzene) afforded 3-85 g of l-t(3~-carbomethoxybiphenyl-4-yl)meth 2-butyl-4-chloro-5-hydroxymethylimidazole (m.p.
162-163), the regioisomer of higher Rf; NMR (200 MHz, CDC13) 8.24 (s, lH): 8.03 (d, lH); 7.76 (d, lH); 7.52 (t, lH); 7.33 (A2B2, 4H); 5.27 (6, 2H);
4.52 (d, 2H); 3.93 (s, 3H); 2.60 (t. 2H); 1.89 (t, lH); 1.67 (quint., 2H); 1.35 (sext., 2H); 0.88 (t, 3H).
151 t 3340~2 PART D: PreparatiOn of l-t(3'-Carbomethoxybiphenyl-4-yl)methYll-2-butyl-5-hydroxymethylimidazole A mixture of 1.00 g of 10S palladium/carbon and 1.00 g of 1-[(3'-carbomethoxybiphenyl-4-yl)methyl~-2-butyl-4-chloro-5-hydroxymethyl imidazole in 20 mL of methanol wa6 6tirred at 25 for five minute6. Hydrogen gas was bubbled into the solution, and the mixture wa6 6tirred under H2(g) (1 atm.) at 25 for 3.5 hour6.
The mixture wa6 filtered, and the re6ulting 601utioD
concentrated in vacuo. Column chromatography (elution:
0-5% methanol/chloroform) furnished 0.33 g of 1-1(3'-carbomethoxybiphenyl-4-yl)methyll-2-butyl-S-hydroxy-methyl imidazole. NMR (200 MHz, DMSO-d6) ~ 8.20 (8, lH): 7.98 (d, 2H): 7.65 (t, 18): 7.41 (A2M2, 4H): 6.80 (6, lH): 5.30 (6, 2H): 5.12 (t, lH): q.37 (d, 2H); 3.90 (6, 3H): 2.52 (t, 2H): 1.51 (quint., 2H): 1.27 (sext., 2H): 0.80 (t, 3H).
The following intermediate6 6hown below were al60 prepared by the procedures described in Part C or Part~ C and D above.
.
~6 ~ N ~ R
?R1 3 ~ ~13 R R R MP(C) n-butyl Cl CH20H4 ~ 162-163 n-butyl Cl CH20H3 ~ (oil)a C\02Me n-butyl H CH20H4 ~ 139-141 C02tBu n-butyl I CH20~4. ~ 125-126 n-butyl CH20H Cl 4 ~ 116-118 C0 Me n-butyl C~l20H Clq ~ lZ2-124 C02tBu a NMR (200 MHz, CDC13) ~ 7.82 (d of d, lH);
7.58 (t of d, lH); 7.44 (t of d, lH); 7.35 (d of d, lH); 7.11 (AzBz, 4H); 5.21 (6, 2H);
4.46 (s, 2H); 2.59 (t, 2H); 1.60 (quint, 2H);
1.29 (sext., 2H); 0.82 (t, 3H).
PART E: Preparation of l-t(3'-Carboxybiphenyl-4-yl)-methyl]-2-butyl-4-chloro-5-hydroxymethyl-imidazole A 601ution of 0.30 g of 1-~(3'-carbomethoxy-biphenyl-4-yl)methyl]-2-butyl-4-chloro-5-hydroxymethyl-imidazole in 16 mL of ethanol and 8 mL of 10~ aqueous sodium hydroxide wa6 refluxed for 5 hour6. After cooling, the reaction mixture was filtered, and the ~olvent was removed in vacuo. The re6idue was di6-solved in water, and the solution wa6 acidified to pH
3.5 u6ing hydrochloric acid. The precipitated 601id wa6 recovered by filtration and recry~tallized from aqueous ethanol to furnish 0.24 g of 1-[(3'-carboxy-biphenyl-4-yl)methyl]-2-butyl-4-chloro-5-hydroxymethyl-imidazole (m.p. 180-181): MMR (200 MHz, DMSO-d6):
8.26 (s, lH); 8.04 (d, lH): 7.77 (d, lH): 7.52 (t, lH); 7.36 tA2M2, 4H); 5.30 (6, 2H); 4.48 (~, 2H);
2.57 (t, 2H); 1.64 (quint., 2H); 1.34 (6ext., 2H);
0.87 (t, 3H).
Example 86 PART A: Preparation of 1-[(3'-Carbomethoxybiphenyl-4-yl)methyl]-2-butyl-4-chloro-5-methoxymethyl-imidazole A fiolution of 5.00 g of 1-[(3'-carbomethoxybi-phenyl-4-yl)methyl]-2-butyl-4-chloro-5-hydroxymethyl-imidazole and 1.0 mL of conc. 6ulfuric acid in 200 mL
of met~anol was refluxed for 20 hours. After cooling, -the solvent was removed in vacuo, and the residue was poured into saturated sodium bicarbonate solution.
The resulting mixture was extracted with methylene chloride, and the combined organic phases were washed 5 with water and brine, dried over anhydrou6 sodium sulfate, filtered, and concentrated in vacuo. Column chromatography on silica gel (elution: 0-20~ ethyl acetate~benzene) furnished 5.35 g of 1-t(3'-carbo-methoxybiphenyl-4-yl)methyl~-2-butyl-4-chloro-5-methoxymethylimidazole: NNR (200 MHz, CDC13):
8.26 (t, lH): 8.03 (d of t, lH); 7.76 (d of t, lH):
7.51 (t, lH): 7.33 (A2M2, 4H); 5.20 (6, 2H); 4.31 (s, 2H); 3.94 (6, 3H): 3.27 (s, 3H): 2.59 (t, 2H);
1.68 (quint., 2H); 1.34 (sext., 2H); 0.87 (t, 3H).
The following intermediates were prepared or could be prepared using the above described procedure.
R6lN~R8 1 3 3 4 0 9 2 ~3 --QR 13 ~ R
R R _ MP(C) C ~ H3 n-butyl Cl CH20CH3q~ Oila N~
- n-butyl Cl CH20CH34~,3 oilb C ~ H3 n-butyl Cl CH20~ 34~ Oilc a -NMR (200 MHz, CDC13) ~ 7.82 (d, lH, J= 7Hz);
7.50 (t, lH, J= 7Hz); 7.38 (t, lH, J= 7Hz):
7.30 (d, lH, J= 7Hz): 7.26 (d, 2H, J= lOHz):
7.00 (d, 2H, J= lOHz): 5.14 (s, 2H): 4.32 (s, 2H): 3.63 (s, 3H): 3.28 (s, 3H): 2.60 (t, 2H, J= 7Hz); 1.70 (t of t, 2H, J= 7,7Hz): 1.36 (t of q, 2H, J= 7,7Hz): 0.89 (t, 3H, J= 7Hz).
b -NMR (200 MHz, CDC13) ~ 7.88 (d of d, lH):
7.63 (t of d, lH): 7.51 (t of d, lH) 7.41 (d of d, lH): 7.17 (A282, 4H); 5.20 (s. 2H):
4.30 (s, 2H); 3.27 (s, 3H); 2.59 (t, 2H):
1. 67 (quint ., 2H); 1.35 (sext., 2H); 0.87 (t, 3H).
` -156 1 3340~2 c -NMR (200 MHz, CDC13) ~ 7.84 (d, lH); 7.53 (t, lH), 7.40 (t, lH): 7.29 (m, 3H): 7.04 (d, 2H), 5.22 (6, 2H); 4.36 (s, 2H); 3.65 (8, 3H); 3.61 (sept., lH), 2.59 (t, 2H): 1.68 (quint., 2H): 1.33 (6ext., 2H): 1.14 (d, 6H):
0.88 (t, 3H).
PART B: Preparation of 1-[(3'-Carboxybiphenyl-4-yl)-methyl]-2-butyl-4-chloro-5-methoxymethyl-imidazole By the procedure described in Example B5, Part ~, 3.35 g of the title compound was prepared from 5.35 g of l-t(3'-carbomethoxy)biphenyl-4-yl)methyl]-2-butyl-4-chloro-5-methoxymethylimidazole: NHR (200 MHz, CDC13) ~ 8.33 (s, lH): 8.11 (d, lH): 7.80 (d, lH): 7.55 (t, lH); 7.34 (A2M2, 4H); 5.21 (8, 2H): 4.32 (s, 2H):
3.27 (6, 3H): 2.63 (t, 2H): 1.68 (quint., 2H): 1.34 (sext., 2H): 0.86 (t, 3H).
Example 87 Preparation of l-t(3l-Carboxybiphenyl-4-yl)methyl]-2-butyl-4-chloro-5-acetoxYmethylimidazole A 601ution of 0.10 g of 1-~(3'-carboxybiphenyl-4-yl)methyl]-2-butyl-4-chloro-5-hydroxymethylimidazole, 5 mg of N,N-dimethylaminopyridine, 0.10 mL of acetic anhydride, and 0.14 mL of triethylamine in 8 mL of tetrahydrofuran was 6tirred for 4.5 hour6 at 25. The reaction mixture was poured into water, and dilute aqueous sodium hydroxide was added until the pH of the solution remained in the range of pH 8-9. The solution was then acidified to pH 3.5 using lOS aqueous hydro-chloric acid and extracted with ethyl acetate. The combined organic phases were washed with brine, dried over anhydrous 60dium sulfate and concentrated.
-157 1 }34092 Column chromatography on 6ilica gel (elution: 0.5%
i-propanol/chloroform) furnished 0.065 g of 1-[(3~-carboxybiphenyl-4-yl)methyl]-2-butyl-4-chloro-5-acetoxymethylimidazole, m.p. 172-173; NMR (200 MHz, DMSO-d6): ~ 8.17 (6, lH): 7.93 (t, 2H); 7,61 (t, lH): 7-43 (A2M2, 4H): 5.32 (6, 2H): 4.99 (8, 2H) 2.60 (t, 2H): 1.76 (6, 3H): 1.53 (quint., 2H): 1.28 (sext., 2H): 0.82 (t, 3H).
ExamPle 88 Preparation of 1-[(3'-Trimethylacetoxymethoxycarbonyl-biphenyl-4-yl)methyl]-2-butyl-4-chloro-5-~ydroxymethyl-imidazole To a 601ution of 1.25 g of 1-[(3l-carboxybiphen-yl-4-yl)methyl]-2-butyl-4-chloro-5-hydroxymet~yli~id-azole in 10 mL of dimethylformamide at 25 wa6 added0.17 g of 60dium methoxide followed after 5 minute6 by 0.45 g of chloromethyl trimethylacetate. The mixture was 6tirred at 25 for 4 day6. The 601vent was removed in vacuo and the re6idue wa~ di6sol~ed in ethyl acetate. This 601ution wa~ washed with water and brine, dried over anhydrou6 sodium 6ulfate, filtered and concentrated. Column chromatography on 6ilica gel afforded 1.38 g of the product a6 a glas~y 601id. NMR (200 MHz, CDC13) ~ 7.87 (d, lH); 7.54 (t, lH); 7.43 (t, lH); 7.29 (d, lH); 7.11 (A2B2, 4H); 5.72 (6, 2H); 5.24 (6, 2H); 4.51 (6, 2H); 2.61 (t, 2H); 2.06 (br 6, lH); 1.68 (quint., 2H): 1.36 (6ext., 2H): 1.17 (6, 9H): 0.88 (t, 3H).
ExamPle 89 PART A: Preparation of 4l-methylbip~enyl-2-carboxylic acid Methyl 4'-methylbiphenyl-2-carboxylate (10.0 g, 44.2 mmol, 1 eq), 0.5 N ~OH in methanol (265.5 mL, 133 mmol, 3 eq), and water (50 mL) were mixed and refluxed under N2. After 5 hour~, the solvent was removed ~n vacuo and water (200 mL) and ethyl acetate (200 mL) added. The aqueous layer was acidified with concentrated hydrochloric acid to a pH of 3 and the layers were 6eparated. The aqueous phase wa6 extracted with ethyl acetate (2 x 200 mL), the organic layer6 collected, dried (MgSO4) and the 601vent removed in vacuo to yield 8.71 g of a white solid;
m.p. 140.0-145Ø NMR (200 M~z, D~SO-d6) ~ 7.72 ~d, lH, J= 7Hz): 7.56 (t, lH, J. 7Hz): 7.45 (d, lH, Jz 7Hz): 7.40 (t, lH, J= 7Hz): 7.25 (6, 4H): 2.36 (8, 3H). Anal. Calcd. for C14H12O2: C, 79.23: H, 5.70. Found: C, 79.22; H, S.47.
PART B: PreParation of 4'-MethYl-2-cyanobiphenyl 4~-Methylbiphenyl-2-carboxylic acid (8.71 g, 41 ~mol, 1 eq) and thionyl chloride (30.0 mL, 411 mmol, 10 eq) were mixed and refluxed for 2 hours. The excess thionyl chloride was removed in vacuo and the residue was taken up in toluene. The toluene wa~
removed by rotary evaporation and thi6 toluene evaporation procedure wa~ repeated to ensure that all of the tbionyl chloride wa~ removed. The crude acid chloride wa~ then added slowly to cold (0C) concentrated NH40H (50 mL) so that the temperature was kept below 15. After 15 minute6 of stirring, water (100 mL) was added and solids precipitated.
The~e were collected, washed well with water and dried under high vacuum over P205 in a des6icator overnight to yield 7.45 g of a white 601id; m.p.
126.0-128.5. NMR (200 MHz, DMSO-d6) ~ 7.65-7.14 (m, lOH); 2.32 (~, 3H). Anal. Calcd. for C14H13NO: C, 79.59; H, 6.20; N, 6.63. ~ound C, 79.29; H, 6.09; N, 6.52.
159 1 3340~2 ~ he above product amide (7.45 g, 35 mmol, 1 eq) and thionyl chloride (25.7 mL, 353 mmol, 10 eq) were mixed and refluxed for 3 bour6. The thionyl chloride was removed using the ~ame procedure a~ de6cribed above. The re6idue wa~ wa~hed with a little hexane which partly ~olubilized the product, but removed tbe impurity a~ well to yield 6.64 9 of white ~olid: m.p.
44.0-47Ø NMR (200 MHz, DMSO-d6) ~ 7.95 (d, lH, J= 8Hz): 7.78 (t, lH, Jz 7Hz); 7.69-7.32 (~, 6H): 2.39 (~, 3H). Anal. Calcd. for C14HllN: C, 87.01; H, 5.74. Found: C, 86.44: H, 5.88.
PART C: PreParation of 4~-bromomet~Yl-2-cyanobiphen 4'-methyl-2-cyanobiphenyl (5.59 g) wa~
brominated in the benzylic po6ition by the procedure in Example 85, Part B u6ing benzoyl peroxide a~ an initiator. The product wa~ recrystallized from ether to yield 4.7 g of product; m.p. 114.5-120Ø NMR
(200 MHz, CDC13) ~ 7.82-7.37 (m, 8H); 4.50 (6, 2H). Anal. Calcd. for C14HlOBrN: C, 61.79: H, 3.70; N, 5.15. Found: C, 6Z.15: H, 3.45; N, 4.98.
PART D: Preparation of 2-n-butyl-4-chloro-1-t2~-cyanobiphenyl-4-yl)methyl~-5-(hydroxymethyl)-imidazole 4'-Bromomethyl-2-cyanobiphenyl (4.6 g) wa~
alkylated onto 2-n-butyl-4-chloro-5-(hydroxymethyl)-imidazole by the procedure de~cribed in Example 1, Part A. Work-up and flash chromatography in 1:1 hexane/ethyl acetate over silica gel to ~eparate the regioi~omeric product6 yielded 2.53 g of the fa~ter eluting i~omer. Recry~talli2ation from acetonitrile yielded 1.57 g of analytically pure product: m.p.
153.5-155.5. NMR (200 MHz, CDC13) ~ 7.82-7.43 (m, 6); 7.12 (d, 2, J= 8Hz); 5.32 (5, 2); 4.52 (~, 2);
-2.62 (t, 2, J= 7Hz): 1.70 (t of t, 2, J= 7,7Hz); 1.39 (t of q, 2, J= 7,7Hz): 0.90 (t, 3, J= 7Hz). Anal.
Calcd- for C22H22ClN3 C, 69-56 H~ 5-84 N~
11.06. Found: C, 69.45: H, 5.89; N, 10.79.
PART E: Preparation of 2-n-butyl-4-chloro-5-hydroxy-methyl-l-[(2'-(lH-tetrazol-5-yl)bipbenyl-4-yl)methyllimidazole 2-n-Butyl-4-chloro-1-~(2'-cyanobiphe~yl-4-yl)-methyl]-5-(hydroxymethyl)imidazole (11.93 g) wa6 con~erted to the above product by the procedure de6cribed in Example 90, Part C. The product wa~
purified by fla6h chromatography in 100% ethyl acetate to lOOS ethanol over 6ilica gel to yield 5.60 g of a light yellow 601id. Recry6tallization from acetonitrile yielded 4.36 g of light yellow cry6tal6 which 6till melted broadly. The cry6tal6 were taken up in 100 mL of hot acetonitrile. The 601id that did not di6601ve was filtered off to yield 1.04 g of product as a light yellow solid: m.p. 183.5-184.5.
Upon cooling, the mother liquor yielded an additional 1.03 g of product a6 a light yellow 601id; m.p.
179.0-180Ø NMR (200 MHz, DMSO-d6) ~ 7.75-7.48 (m, 4H): 7.07 (d, 2H, J= 9Hz); 7.04 (d, 2H, J= 9Hz):
5.24 (s, 2H): 5.24 (b6, lH): 4.34 (6, 2H); 2.48 (t, 2H, J= 7Hz): 1.48 (t of t, 2H, J= 7,7Hz); 1.27 (t of q, 2H, J= 7,7Hz); 0.81 (t, 3H, J= 7Hz). Anal. Calcd.
for C22H23ClN60: C, 62.48; H, 5.48; Cl, 8.38.
~ound for the 601id6 which did not di6601ve in 100 mL
of acetonitrile: C, 62.73; H, 5.50; Cl, 8.26. ~ound for the 601id6 obtained from the mother liguor: C, 62.40; H, 5.23: Cl, 8.35.
161 1 334~2 Example 90 PART A: Preparation of 2-n-Butyl-4-chloro-5-chloro-methyl-l-t(2'-cyanobiphenyl-4-yl)methyl]-imidazole-HCl salt 2-n-Butyl-4-chloro-5-hydroxymethyl-1-[(2'-cyanobiphenyl-4-yl)methyl~imidazole (15.00 q, 39.3 mmol, 1 eq) was converted to the chloride by the procedure in Example 1, Part B. The reaction time was 5 hours. The crude solid product wa~ was~ed with ether to remove the yello~ color. The solid white powdery product wa6 then dried under high vacuum, yield 10.02 9; m.p. 152.0-154Ø NHR (200 MHz, CDC13) ~ 7.85-7.46 (m, 6H): 7.20 (d, 2H, J,lOHz);
5.47 (8, ZH); 4.50 (6, 2H): 3.06 (t, 2H, J~ 7Hz): 1.82 (t of t, 2H, J= 7,7Hz): 1.45 (t of q, 2~, J. 7,7Hz);
0.94 (t, 3H, J= 7Hz). Ma66 Calcd. for C22H21C12N3: 397.1113. Found: 397.1105.
PART B: Preparation of 2-n-Butyl-4-chloro-1-t(2~-cyanobiphenyl-4-yl)methyl]-5-(methoxymethyl)-imidazole 2-n-Butyl-4-chloro-5-chloromethyl-1-1(2'-cyano-biphenyl-4-yl)methyl]imidazole-HC1 6alt (5.00 g, 11.5 mmol, 1 eq), 60dium methoxide (1.37 g, 25.3 mmol, 2.2 eq) and methanol (100 mL) were mixed and stirred for 3 days. The solvent was removed in vacuo and ethyl acetate (200 mL) and water (200 mL) added. The layer6 were separated and the aqueous layer was extracted with ethyl acetate (2 x 200 mL). The organic layer6 were dried (MgS04), the 601vent removed in vacuo and the re8idue flash c~romatographed over silica gel in 1:1 hexane/ethyl acetate to yield 4.06 g of a clear light yellow oil. NMR (200 MHz, CDC13) ~ 7.B2-7.43 (m, 6); 7.10 (d, 2H, J= 7Hz):
5.23 (s, 2H); 4.32 (s, 2H); 3.30 (s, 3H): 2.60 (t, 2H, 162 1 3340~2 J= 7Hz); 1.70 (t of t, 2H, J= 7,7Hz); 1.38 (t of q, 2H, J= 7,7Hz): 0.89 (t, 3H, J= jHZ). Anal. Calcd. for C23H24ClN30: C, 68.11; H, 6.54; Cl, 9.58.
Found: C, 68.70; H, 6.11; Cl, 9.51. Ma~s Calcd. for C23H24ClN30: 3g3.1607. Found: 393.1616.
PART C: Preparation of 2-n-Butyl-4-chloro-5-methoxy-methyl-l-t(2~-(lH-tetrazol-5-yl)biphenyl-4-methYl~imidazole 2-n-Butyl-4-chloro-1-~2~-cyanobiphenyl-4-yl)methyl]-5-methoxymethyl)imidazole (3.94 g, 10 mmol, 1 eq), ~odium azide (1.95 g, 30 mmol, 3 eq), and ammonium chloride (1.60 g, 30 mmol, 3 eq) were mixed and 6tirred in DMF (150 mL) in a round bottom fla~k connected to a ref 1UY condenser under N2. An oil bath with a temperature controller wa~ then u~ed to heat the reaction at 100C for 2 days, after which the temperature was rai~ed to 120C for 6 day6. The reaction was cooled and 3 more equivalent6 each of ammonium chloride and ~odium azide were added. The reaction was again heated for 5 more day~ at 120C.
The reaction was cooled, the inorganic ~alts filtered, and the filtrate solvent removed in vacuo. Water (200 mL) and ethyl acetate (200 mL) were added to the residue and the layers were 6eparated. The aqueous layer was extracted with ethyl acetate (2 x 200 mL), the organic layers were collected, dried (MgS04) and the 601vent removed in vacuo, to yield a dar~ yellow oil. ~lash chromatography in 100% ethyl acetate yielded 3.54 g of a white qla~s. NMR (200 MHz, CDC13) ~ 7.83 (d, lH, J= 7Hz): 7.59 (t, lH, J=
7Hz); 7.50 (t, lH, J= 7Hz): 7.39 (d, lH, J= 7Hz): 7.03 (d, 2H, J= 8Hz); 6.73 (d, 2H, J= 8Hz); 5.0B (s, 2H);
4.12 (6, 2H): 3.18 (s, 3H); 2.32 (t, 2H, J= 7Hz); 1.52 (t of t, 2H, J= 7,7Hz); 1.28 (t of q, 2H, J= 7,7Hz);
0.83 (t, 3H, J= 7Hz). Ma66 Calcd. for C23H25ClN60:436.1178. ~ound: 436.1750.
CAUTION~ The above reaction althougb uneventful in our S hand6 can be potentially explosivel Crystals that sublimed and collected in the reflux condenser during the reaction were not analyzed, but potentially could be ammonium azide~ Hydrazoic acid, which is shoc~
6en6itive, could al60 be potentially produced during the reaction and wor~-up. Extreme care should be taken~
ExamPle 91 5 PA~T A: Preparation of 2-butyl-4(5)-hydroxymethyl-5(4)-nitroimidazole To a solution of 5.75 g of 2-butyl-4(5)-hydroxymethylimidazole (prepared as de6cribed in U.S.
4,355,040) in 200 mL of aqueous methanol at 25C was added concentrated hydrochloric acid until the pH of the solution reached pH 3. The solvent was then removed in vacuo, and the re6idue wa6 di6601ved in 100 mL of chloroform. To thi6 601ution at 25 was added dropwi6e 15.0 mL of tbionyl chloride, and the mixture was refluxed for 1 hour. After cooling, the solvent and exce66 thionyl chloride were removed in vacuo to provide a viscou6 yellow oil.
To a solution of 20 mL of concentrated sulfuric acid and 10 mL of concentrated nitric acid at -10 wa6 added a 601ution of the yellow oil, prepared above, in 10 mL of concentrated 6ulfuric acid. The re~ulting mixture was heated on a steam bath for 2 hours. After cooling, the reaction mixture wa~ poured onto water-ice, and the resulting emulsion was extracted with chloroform. The combined organic phases were 164 1 334 Oq2 wa6hed with water and brine, dried over anhydrou6 ~ ~60dium 6ulfate, filtered, and concentrated in vacuo.
The residue was then di6601ved in 100 mL of 1:12-propanol/water. The 601ution wa6 then refluxed 5 for 16 bour~. Finally, after cooling, the colution wa6 concentrated in vacuo. Column chromatoqraphy (elution: methanol~chloroform) afforded 2.64 g of 2-butyl-4(5)-hydroxymethyl-5(4)-nitroimidazole. NMR
(200 MHz, DMS0-d6): ~ 12.92 (br 8, lH); 5.80 (br t, lH); 4-82 (d, 2H): 2.60 (t, 2H); 1.61 (quint., 2H):
1.25 (6ext., 2H): 0.84 (t, 3H).
PART B: Preparation of 1-~(2'-tert-butoxycarbonyl-biphenyl-4-yl)methyl~-2-butyl-5-hydroxy-methYl-4-nitroimidazole Thi6 compound wa6 prepared according to the procedure de6cribed in Example 85, Part C. From 2.64 g of 2-butyl-4(5)-hydroxymethyl-5(4)-nitroimidazole and 5.55 g of tert-butyl 4'-bromomethylbipbenyl-2-carboxylate there wa6 obtained 2.05 g of 1-t(2'-tert-butoxycarbonylbiphenyl-4-yl)methyll-2-butyl-5-hydroxy-methyl-4-nitroimidazole. NMR (200 MHz, CDC13): ~
7.79 (d, lH): 7.45 (m, 2H): 7.33 (d, lH): 7.28 (d, lH); 7.03 (d, 2H): 5.34 (6, 2H): 4.87 (6, 2~): 2.81 (br 6, lH): 2.67 (t, 2H): 1.73 (guint., 2H): 1.37 (6ext. 2H): 1.27 t6, 9H): 0.90 (t, 3H).
PART C: Preparation of l-t(2'-carboxybiphenyl-4-yl)-methyl]-2-butyl-5-bydroxymethyl-4-nitroimidazole A 601ution of 1.98 g Of lt(2'-tert-butoxy-carbonylbiphenyl-4-yl)methyl]-2-butyl-5-hydroxymethyl-4-nitroimidazole, 20 mL of trifluoroacetic acid, and 20 mL of methylene chloride wa6 6tirred at 25 for 1 hour. At thi6 point, the 601ution wa6 poured into water. The resulting mixture was adjusted to pH 3 using 10% 60dium hydroxide solution and then extracted with chloroform. The combined organic pba6es were washed with brine, dried over anhydrous magne6ium 6ulfate, filtered, and concentrated in vacuo. Column chromatography (elution: methanol~chloroform) provided 1.49 g of 1-t(2'-carboxybiphenyl-4-yl)-methyl]-2-butyl-S-hydroYymethyl-4-nitroimidazole: m.p.
204-205.5. NMR (200 MHz, DMS0-d6): ~ 7.71 ~d, lH); 7.56 (t, lH): 7.43 (t, lH): 7.32 (m, 3H): 7.15 (d, 2H): 5.63 (br 6, lH): 5.42 (6, 2H): 4.83 (6, 2H):
2.54 (t, 2H): 1.50 (quint., 2H): 1.24 (sext., 2H):
0.76 (t, 3H).
ExamPle 92 PART A: Preparation of l-t(2'-tert-butoxycarbonyl-biphenyl-4-yl)methyl]-2-butyl-4-iodo-5-(2-methoxYethoxymethoxymethyl~imidazole To a solution of 5.56 mL of 1.6 M n-butyl-lithium/hexane in 80 mL of tetrahydrofuran at 0 wa6 added dropwi6e 1.15 mL of t-butanol. To the solution was added 3.28 g of 1-~(2'-tert-butoxycarbonylbiphenyl-4-yl)methyl]-2-butyl-5-hydroxymethyl-4-iodoimidazole followed by 1.15 mL of 2-methoxyethoxymethyl chloride. The resulting solution wa6 6tirred at 25 for 16 hour6. The mixture was diluted wit~ diet~yl ether, washed with water and brine, dried over anhydrou6 60dium sulfate, filtered and concentrated.
Column chromatography afforded 2.61 g of 1-[2'-tert-butoxycarbonylbiphenyl-4-yl)methyl]-2-butyl-4-iodo-5-(2-methoxyethoxymethoxymethyl)imidazole. NMR
(200 MHz, CDC13): ~ 7.78 (d, lH): 7.43 (m, 2H);
7.28 (m, 3H); 6.98 (d, 2H): 5.26 (s, 2H); 4.69 (s, 2H); 4.45 (s, 2H): 3.68 (m, 2H); 3.57 (m, 2H); 3.37 (s, 3H); 2.58 (t, 2H); 1.67 (quint., 2H); 1.3q (sext., 2H); 1.26 (s, 9H): 0.87 (t, 3H).
-PART B: Preparation of l-t(2'-tert-butoxycarbonyl-biphenyI-4-yl)methyl~-2-butyl-5-(z-methoxy- ---ethoxymethoxymethyl)-4-trifluoromethyl-imidazole To a su6pension of 22.4 g of cadmium powder powder in 50 mL of dimethylformamide at 25 was added dropwi6e 8.60 mL of bromochlordifluoromet~ane. The resulting mixture was stirred at 25 for 2 hours and then was filtered through a medium-fritted Schlen~
funnel under nitrogen pressure to provide a dar~ brown 601ution of t~e trifluoromethyl cadmium reagent.
To a mixture of 15 mL of the above 601ution and 20 mL of hexamethylphosphoric triamide at 0 wa6 added 2.10 g of copper(I)bromide followed by 2.61 g of 1-t(2'-tert-butoxycarbonylbiphenyl-4-yl)methyl~-2-butyl-4-iodo-5-(2-methoxyethoxymethoxymethyl)imidazole in 5 mL of dimethylformamide. The reaction mixture was stirred at 70-75 for 6 hours. After cooling, t~e mixture wa6 diluted with water and then extracted with methylene chloride. The combined organic phases were washed with water and brine, dried over anhydrous 60dium 6ulfate, filtered, aDd concentrated. Column chromatography (elution: ethyl acetate/hexane) afforded 2.30 9 of 1-t(2'-tert-butoxycarbonylbiphenyl-4-yl)methyl~-2-butyl-5-(2-methoxyethoxymethoxymethyl)-4-trifluoromethylimidazole. NMR (200 ~Hz, CDC13):
7.79 (d, lH): 7.46 (m, 2H): 7.28 (m, 3H): 7.00 (d, 2H); 5.28 (6, 2H); 4.71 (s, 2H): 4.5B (s, 2H): 3.66 (m, 2H); 3.54 (m, 2H): 3.38 (8, 3H): 2.62 (t, 2H):
1.70 (quint., 2H): 1.36 (sext., 2H): 1.27 (s, 9H);
0.88 (t, 3H).
PART C: Preparation of l-t(2'-carboxybiphenyl-4-yl)-methyll-2-butyl-5-hydroxymethyl-4-trifluoro-methylimidazole A solution of 2.30 9 of 1-~(2~-tert-butoxy-carbonylbiphenyl-4-yl)methyl]-2-butyl-5-(2-methoxy-167 I 3340~2 ethoxymethoxymethyl)-5-trifluoromethylimidazole in 200 mL of 1.5 M aqueous tetrafluoroboric acid/acetonitrile was stirred at 25 for 18 hours, and then the mixture was poured into water. The resulting aqueous solution was adjusted to pH 3 employing saturated sodium bicarbonate solution and then was extracted with chloroform. The combined organic phases were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated. Column chromatography (elution: methanol/chloroform) provided 1.38 g of l-t(2l-carboxybiphenyl-4-yl)methyl]-2-butyl-5-hydroxy-methyl-4-trifluoromethylimidazole (m.p. 198-199.5).
NMR (200 MHz, DMS0-d6): ~ 7.75 (d, lH); 7.54 (t, lH); 7.43 (t, lH); 7.32 (m, 3H); 7.10 (d, 2H); 5.36 (s, 2H); 4.51 (s, 2H); 2.56 (t, 2H); 1.56 (quint., 2H); 1.30 (sext., 2H); 0.83 (t, 3H).
Example 93 PART A: Preparation of 4-azidomethyl-2'-methoxy-carbonYlbiphenyl To a stirred solution of 4-bromomethyl-2'-methoxycarbonylbiphenyl (150 g, 0.49 mol) in dry DMF
(500 ml) was added NaN3 (80 g, 1.23 mol, 2.5 eq).
The mixture was stirred at room temperature overnight (ca. 18 hours), filtered, and the filtrate was partitioned between ethyl acetate and H20 (500 ml each). The organic phase was washed twice more with H20, once with saturated aqueous NaCl solution and dried over anhydrous magnesium sulfate before being filtered and concentrated to leave 111.3 g (85%) of a yellow oil, used in the following step without further purification. NMR (CDC13, TMS, ~) 7.9-7.1 (m, 8H); 4.35 (s, 2H): 3.55 (s, 3H) IR Vmax 2487 cm 1, PART B: Preparation of 4-aminomethyl-2~-methoxy-carbonylbiPhenYl hYdrochloride The azido compound prepared above was di6solved in liter of methanol. The 601ution was divided into three equal volumes and placed in 500 ml Parr bottles.
To each flask was added 6.7 g of 5% Pd on carbon (Caution: Pyrophoricl add under a N2 atmosphere).
The fla6ks were 6ha~eD on a Parr hydroqenator under 40-50 psi H2 for 4-5 hour6 (oYernight i6 al60 acceptable). The mixture was ~uction filtered through a bed of Celite~ and the filtrate was concentrated to leave a vi6cou6 yellow re6idue (88 g). This wa6 di6solved in EtOAc (500 ml) to which wa6 added with ~tirring a solution of EtOAc ~aturated with an~ydrous HCl (100-150 ml) until precipitation wa6 complete.
The amine hydrochloride as produced wa6 6uction filtered, washed with EtOAc and hexane6 and dried under vacuum to afford 48.5 g (40% overall from the bromide) white solid: m.p. 204-208. NMR (CDC13,-CD30D; TMS) ~ 7.9-7.25 (m, 8H); 4.2 (6, 2H);
4.1-3.8 (br, 3H; 6hifts in D2O); 3.6 (6, 3H). HRMS
calcd. for C15H15NO2 (free base); M/Z 241.1103;
Found: M/Z: 241.1045.
PART C: Preparation of 1-[(2'-carboxybiphenyl-4-yl)-methyl~-2-PropYlthio-s-hydroxymethylimidazole The title compound wa6 prepared from methyl 4'-aminomethylbipbenyl-2-carboYylate by the procedures described in Example6 72, A and B, and 85E; m.p.
194-195.
The 4-biphenylmethyl compounds in Table 6 were prepared or could be prepared by the procedure6 illustrated in Examples 85-92 or by procedures previously described.
Table 6 1 334092 N ~
R6~N ~R8 ~ - QR13 No. R R7 R X ~ MP(-C) 94 n-butyl Cl CH20H 4 ~ 168-169.5 95 n-butyl CH20H Cl 4 ~ ~ 197-198 96 n-butyl H CH20H 4 ~ 154-155 C ~ (amorphous 97 n-butyl H CH20H 4 ~ solid) 98 n-butyl Cl CH20CH3q ~ 166.5-169.0 99 n-bu~yl Cl CH2OCH(CH3)2 4 ~ 156-158 Table 6 (continued) 1 3 ~ 4 0 9 2 ~ R
Ex 6 _ _ HP(-C) _ - C02H
100 n-butyl Br CH20H 4 ~ 175-178 C~
101 n-butyl F CH20H 4 ~
Co2H
102 n-butyl I CH20H 4 ~ 165 (dec) C~
103 OCH2 Cl CH20H 4 C~
104 ~ C1 CH20H 4 ~3 c~
105 n-butyl CH20H I 4~ 205 (dec) 106 n-butyl Cl CH20H 4 ~ 185-186 107 ethyl Cl CH20H 4~ 153-156 T~ble 6 (continued) 1 3 3 4 0 9 2 _~R 1 3 No. R R R ~P(-C) 108 n-propyl Cl CH2OH 4 ~ 198-200 109 n-pentyl Cl CH2OH 4 ~ (amorphous ~ ~olid) 110 n-hexyl Cl CH2OH 4 ~ 84-88 Co2H
111 n-butyl Cl CH2SH
Co2H
112 n-bu-yl Cl CH2O
Table 6 (continued) I 33409~
~R13 Ex. 6 R R X ~ HP(C) N-N
113 n-propyl Cl CH20H 4 ~ (amorphous solid) I \
~ ~ ~H
114 n-propyy Cl CHO 4 ~ (amorphous ~ solid) 115 n-butyl Cl CH2C02H 4 ~ ~ 221-222 116 n-butyl Cl CH(CH3)C02H 4 ~ 118-120 C~02H
117 n-butyl CH20H N02 4 ~ 154-157 /N-N
N~,NH
118 n-butyl CH OH Cl ~ (white 2 4 ~ \~ powder) N-N
N~,NH
119 n-buty~. No2 CH20H
T~hle 6 (continued) l 3 3 4 Oq 2 E~_ R6 Rl R8 ~ R13 MP (C) 120 n-butyl Cl N-N NN~
121 n-butyl Cl CH20COCH3 C02H 157-159 122 n-butyl Cl ~ CO2H
CH2OCOCH2CH2 <j=j~ _~
123 N-C4HgS H CH20H C ~H 190-191 4 ~
CH2S H CH20H ~ 1995 5-a -NMR (200 MHz, DMSO-d,) ~ 7.69 (dd, lH);
7.54 (d of t, lH)j 7.43 (d of t, lH); 7.33 (d, lH); 7.16 (A2B2, 4H); 6.76 (s, lH);
5.24~(s, 2H); 4.34 (s, 2H); 2.50 (t, 2H);
1.49 (quint, 2H); 1.25 (sext, 2H); 0.80 (t, 3H) 1 3343q2 b -NMR (200 MHz, DMSO-d6) ~ 7.70 (d, lH), 7.55 (t, lH), 7.42 (t, lH), 7.28 (m, 3H), 7.10 (d, 2H), 5.28 (~, 2H), 4.34 (~, 2H), 2.49 (t, 2H), 1.49 (m, 2H), 1.18 (m, 4H), 0.79 (t, 3H).
c -NMR (200 MHz, CDC13~CD30D): ~
7.82-6.93 (m, 8H): 5.21 (~, 2H): 4.47 (~, 2H): 2.55 (t, J= 7.5bz, 2H): 1.70-1.59 (m, 2H): 0.92 (t, J= 7.5 ~z, 3H).
d -NMR (200 MHz, CDC3) 9.65 (~, lH):
7.95-6.96 (m, 8H): 5.51 (~, 2H): 2.59 (t, J-7.5 hz, 2H): 1.70-1.63 (m, 2H): 0.92 (t, J=
7.5 hz, 3H).
e -NMR (Z00 MHz, CDC13) ~ 7.76 (d, lH, J=
7Hz): 7.57 (t, lH, J. 7Hz): 7.49 (t, lH, J=
7Hz): 7.40 (d, lH, J= 7Hz): 7.02 (d, 2H, J=
8Hz): 6.81 (d, 2H, J= 8Hz): 5.03 (~, 2H):
4.28 (~, 2H): 2.46 (t, 2H, J= 7Hz): 1.47 (t of t, 2H, J= 7,7Hz): 1.17 (t of q, 2H, J=
7,7Hz): 0.73 (t, 3H, J= 7Hz).
Example 125 Preparation of 1-[(2'-Carboxybiphenyl-4-yl)methyl]-2-butyl-4-chloroimidazole-5-carboxaldehYde A mixture of 1.46 g of 1-[2'-carboxybiphenyl-4-yl)methyl]-2-butyl-4-chloro-5-hydroxymethylimidazole and 7.30 g of activated mangane~e dioxide in 40 ml of tetrahydrofuran was ~tirred at 25C for S day6. The mixture wa~ filtered through Celite~, and the filtrate wa~ concentrated in vacuo. Column chromatography on 6ilica gel (elution: 2-10~ methanol/-chloroform) followed by recrystallization from ethyl acetate afforded 0.71 g of 1-t(2'-carboxybiphenyl-4-yl)methyl]-2-butyl-4-chloroimidazole-5-carboxaldehyde (m.p. 154-158C (dec.)). NMR (200 MHz, DMSO-d6) ~
12.85 (br 8, lH), 9.77 (~, lH), 7.77 (d, lH), 7.62 (t, lH), 7.50 (t, lH), 7.40 (d. lH), 7.26 (A2B2, 4H), 5.67 (8, 2H), 2.70 (t, 2H), 1.56 (quint., 2H), 1.28 (6ext., 2H), 0.83 (t, 3H).
Example 126 1 Preparation of Methyl l-t(2'carboYybiphenyl-4-yl)-methYl~-2-butYl-4-chloroiraidazole-5-carboxylate To a mixture of 1.45 g of 1-t(2'-carboxybiphenyl-4-yl)methyl]-2-butyl-4-chloroimidazole-5-carboxaldehyde and 0.91 g of sodium cyanide in 20 ~L of methanol at 25C wa~ added 0.32 mL of acetic acid followed by 7.25 g of mangane6e dioxide. The re~ulting mixture was stirred at 25C for 40 hours. The reaction mixture wa~ filtered through Celite~, and the filtrate diluted with water. The aqueous solution wa~ adju6ted to pH 3 u~ing hydrochloric acid and extracted with methylene chloride. The combined organic pha~e6 were wa~hed with brine, dried over anhydrou~ sodium sulfate, filtered, and concentrated. The crude product was recry6tallized from diethyl ether to afford 0.90 g of methyl 1-t(2'-carboxybiphenyl-4-yl)-methyl]-2-butyl-4-chloroimidazole-5-carboxylate (m.p.
154-155C). NMR (200 MHz, DMS0-d6): ~ 12.75 (br 8, lH), 7.73 (d, lH) 7.58 (t, lH), 7.46 (t, lH), 7.34 (m, 3H), 7.07 (d, 2H), 5.63 (6, 2H), 3.78 (8, 3H), 2.67 (t, 2H), 1.56 (quint., 2H), 1.29 (sext., 2H), 0.83 (t, 3H).
-Example 127 1 3 3 4 0 q 2 Preparation of l-t(2'-Carboxybiphenyl-4-yl)methyl]-2-butyl-4-chloroimidazole-5-carboxamide Anhydrous ammonia was bubbled into 40 mL of i-propanol until the solvent was saturated. To this solution at 25C was added 0.49 g of powdered sodium cyanide, then O.B0 g of 1-~(2'-carboxybiphenyl-4-yl)-methyl]-2-butyl-4-chloroimidazole-5-carboxaldehyde, and finally 3.48 g of mangane~e dioxide. Thi6 mixture 10 was stirred at 25C for 65 hour6. The reaction mixture was filtered through Celite~, and the filtrate concentrated in vacuo. The re~idue was dis601ved in water, and the aqueous solution was adjusted to pH 3 usinq hydrochloric acid and then extracted with methylene chloride. The combined organic phases were wa6hed with brine, dried over anhydrous sodium ~ulfate, filtered, and concentrated.
Column chromatography on silica gel (elution: 0-10%
i-propanol (chloroform) provided 0.22 g of l-t(2'-carboxybiphenyl-4-yl)methyl]-2-butyl-4-chloroimidazole-5-carboxamide as a white 601id (m.p. 200-202C). NMR
(200 MHz, DMSO-d6): ~ 12.74 (br s, lH); 7.71 (d, 2H); 7.56 (t, lH), 7.48-7.30 (m, 6H): 7.09 (s, 2H):
5.57 (s, 2H): 2.59 (t, 2H): 1.51 (quint., 2H): 1.26 (sext. 2H): 0.80 (s, 3H).
ExamPle 128 PA~T A: Preparation of l-t(2'-Carbomethoxybiphenyl-4-- yl)methyl]-2-butyl-4-chloroimidazole-5-carboxaldehyde A mixture of 2.06 g of 1-t(2'-carbomethoxy-bip~enyl-4-yl)methyl]-2-butyl-4-chloro-5-hydroxymethyl-imidazole and 3.08 g of activated manganese dioxide in 20 mL of methylene chloride at 25C was stirred for 40 hours. The reaction mixture was filtered through ~
Celite~, and the filtrate concentrated in vacuo.
Column chromatography (elution: ethyl acetate/benzene) provided 1.15 g of 1-1(2'-carbo-methoxybiphenyl-4-yl)methyll-2-butyl-4-chloro-imidazole-5-carboxaldehyde. NMR (200 MHz, CDC13) 9.76 (s, lH); 7.83 (d of d, lH); 7.52 (t of d, lH); 7.40 (t of d, lH); 7.31 (d of d, lH); 7.17 (A2B2, 4H); 5.58 (8, 2H); 3.63 (8, 3H); 2.67 (t, 2H); 1.70 (quint., 2H); 1.38 (sest., 2H); 0,90 (t, 3H).
PART B: Preparation of 1-~(2-Carbomethoxybiphenyl-4-yl)methyl]-2-(1-bromobutyl)-4-cbloroimidazole-5-carboxaldehYde A mixture of 1.12 g of l-t(2~-carbometboYybi-phenyl-4-yl)methyl]-2-butyl-4-chloroimidazole-5-carboxalde~yde and 0.49 g of N-bromosuccinimide in 40 mL of CC14 was irradiated (W-lamp, pyrex filter) for 0.5 ~our6. The reaction mixture wa~ filtered, and the filtrate was concentrated in vacuo. Column chromatograpby (elution: ethyl acetate/benzene) afforded 0.54 g of 1-~(2'-carbomethoxybiphenyl-4-yl)-methyl]-2-(1-bromobutyl)-4-chloroimidazole-5-carbox-aldehyde. NNR (200 MHz, CDC13) ~ 9.87 (6, lH);
7.86 (d, lH): 7.5g (t, lH); 7.46 (t, lH): 7.30 (m, 3H); 7.11 (d, 2H); 6.16 (d, lH); 5.32 (d, lH); 4.79 (t, lH); 3.65 (6, 3H): 2.32 (m, 2H): 1.34 (sext., 2H);
0.83 (t, 3H).
PART C: Preparation of l-t(2'-Carbomethoxybiphenyl-4-yl)methyl]-2-(1-trans-butenyl)-4-chloro-imidazole-5-carboxaldebYde A 601ution of 0.54 g of 1-1(2'-carbomethoxy-biphenyl-4-yl)methyl]-2-(1-bromobutyl)-4-chloro-imidazole-5-carboxaldehyde and 0.33 mL of 1,8-35 diazabicyclol4.5.0]undec-7-ene in 10 mL of tetrahydrofuran was 6tirred at 25C for 18 hour6. the reaction mixture was diluted with diethyl ether, wa6hed with dilute hydrochloric acid, water, and brine, dried over anhydrous 60dium 6ulfate, filtered, and concentrated in vacuo. Column chromatography (elution:ethyl acetate/benzene) furni6hed 0.26 g of ~ 2'-carbomethoxybiphenyl-4-yl)methyl]-2-(l-tran6-butenyl)-4-chloroimidazole-S-carboxaldehyde. NMR (200 MHz, CDC13~ ~ 9.75 (6, lH); 7.82 (d, lH); 7.51 (t, lH); 7.40 (t, lH); 7.33-7.07 (m, 6H); 6.27 (d, lH);
5.62 (6, 2H): 3.62 (6, 3H): 2.30 (quint., 2H); 1.09 (t, 3H).
PART D: Preparation of l-t(2'-Carbomethoxybiphenyl-4-yl)methyl~-2-(l-tran6-butenyl)-4-chloro-S-hydroxymethylimidazole To a 601ution of 0.26 g of 1-[(2'-carbomethoxybi-phenyl-4-yl)methyll-2-(l-tran6-butenyl)-4-chloro-imidazole-S-carboxaldehyde in 10 mL of methanol at 0C
wa6 added 0.24 g of 60dium borohydride portionwi6e over O.S hour6. The mixture wa6 6tirred for an additional 0.5 hour6 at 0C and then poured into a 601ution at 10% 60dium hydroxide in water. The resulting mixture was extracted with ethyl acetate, and the combined orqanic pha6e6 were wa6hed with brine, dried over anhydrou6 60dium 6ulfate, filtered, and concentrated in vacuo. Column chromatography (elution:ethyl acetate/benzene) provided 0.23 g of l-t2~-carbomethoxybiphenyl-4-yl)methyl-2-(l-tran6-butenyl)-4-chloro-5-hydroxymethylimidazole. NMR (200 MHz, CDC13) ~ 7.84 (d, lH); 7.53 (t, lH): 7.40 (t, lH): 7.29 (m, 3H): 7.08 (d, 2H): 6.86 (d of t, lH):
6.17 (d, lH): 5.30 (6, 2H): 4.54 (br 6, 2H): 3.63 (6, 3H): 2.23 (quint., 2H); 1.04 (t, 3H).
- 1 3340~2 PART E: Preparation of l-t(2~-carboxybiphenyl-4-yl) methyl~-2-(1-trans-butenyl)-4-chloro-5-hydroxymethylimidazole Thi~ compound was prepared according to theprocedure de6cribed in Example 85, Part E. From 0.23 g of l-t(2'-carbomethoxybiphenyl-4-yl)methyl~-2-(1-tran6-butenyl)-4-chloro-5-hydroYymethylimidazole there was obtained 0.16 g of 1-t(2'-carboxybiphenyl)-4-yl)methyl~-2-(l-tran6-butenyl)-4-chloro-5-hydroxy-methylimidazole (m.p. 198.5-199.5C). NMR (200 MH2, DMS0-d6) ~ 7.71 (d, lH): 7.56 (t, lH): 7.44 (t, lH): 7.32 (m, 3H): 7.11 (d, 2H): 6.62 (d of t, lH):
6.39 (d, lH): 5.38 (8, 2H); 5.33 (br 6, lH): 4.35 (br 6, 2H); 2.18 (quint., 2H); 0.99 (t, 3H).
ExamPle 129 Preparation of l-t(2'-Carboxybiphenyl-4-yl)methyl]-2-(l-tran6-butenYl)-4-chloroimidazole-5-carboxaldehyde Thi6 compound was prepared according to the procedure of Example 125. From 0.50 g of 1-t(2'-carboxybiphenyl-4-yl)methyl~-2-(1-trans-butenyl)-4-chloro-S-hydroxymethylimidazole and 2.50 g of mangane6e dioxide wa6 obtained 0.24 g of 1-t(2'-carboxybiphenyl-4-yl)methyl~-2-(l-tran6-butenyl)-4-chloroimidazole-5-carboxaldehyde (m.p. 164-166C).
NMR (200 MHz, DMS0-d6) ~ 12.79 (br 6, lH); 9.70 (s, lH); 7.72 (d, lH); 7.57 (t, lH); 7.46 (t, lH);
7.33 (m, 3H); 7.15 (d, 2H), 7.01 (d of t, lH); 6.65 (d, lH); 5.71 (8, 2H); 2.28 (quint., 2H); 1.04 (t, 3H).
180 l 334092 The compounds in Table 7 were prepared or could be prepared empioying the procedures described in Examples 125-129 or by procedures described previously.
Table 7 N
R6~N ~
~ ~ - Rl3 .. R13 Ex. ~
No. R6 R7 R8 MP(C) 130 n-butyl H CHO 4- ~ (amorphousa solid) 131 n-butyl CF3 CHO 4- ~ 132-134 ~N~
N ~ 127.5-131.5 132 n-butyl C1 CHO
N~N~NH
133 n-butyl CF3 CHO h~ (amorphous ~ solid)b ,. !~.
Table 7 (continued) Rl3 1 334092 x~
Ex.
No. R6 R' R3 MP(C) -- ,, C~
134 n-butyl C1 CONHCH3 4 ~ (solid) 135 n-butyl Cl CON(CH3)2 4 ~ (solid) 136 CH3CH=CH- C1 CH2OH 4 137 CH3CH2CH=CH- CF3 CH2OH 4 ~ 217-219 138 CH3CH2CH=CH- Cl CHO 4 ,N~
139 CH3Ch2CH=CH- Cl CH2OH N ~ (amorphoue solid ) , N~
N~
140 CH3CH2CH=CH- Cl CHO 4 a -NMR (200 MHz, DMSO-d6) ~ 12.76 (br 6, lH); 9.67 (6, lH): 7.93 (s, lH); 7.71 (d, lH); 7.55 (t, lH); 7.43 (t, lH); 7.30 (m, 3H); 7.06 (d, 2H); 5.63 (6, 2H); 2.67 (t, 2H); 2.57 (quint., 2H); 2.27 (6ext. 2H); 0.81 (t, 3H).
b -NMR (200 MHz, DMSO-d6) ~ 12.75 (br 6, lH); 8.10 (br ~uart., lH); 7.72 (d, lH); 7.57 (t, lH); 7.45 (t, lH); 7.32 (m, 3H); 7.10 (d, 2H): 5.51 (6, 2H); 2.75 (d, 3H); 2.58 (t, 2H);
1.52 (quint., 2H): 1.27 (6ext., 2H): 0.81 (t, 3H).
c -NMR (200 HHz, DMSO-d6) ~ 12.77 (br 6, lH): 7.73 (d, lH): 7.57 (t,lH); 7.45 (t, lH):
7.33 (m, 3H) 7.09 (d, 2H): 5.20 (br 6, 2H):
2.83 (6, 3H): 2.73 (t, 2H): 2.66 (6, 3H):
1.63 (quint., 2H): 1.36 (6ext., 2H): 0.89 (t, 3H).
-PART A: Preparation of l-t2'-Aminobiphenyl-4-yl)-methyl~-2-butyl-9-chloro-S-methoxymethyl-imidazole A 601ution of 4.40 g of 1-t(2~-nitrobiphenyl-4-yl)methyl]-2-butyl-4-chloro-5-methoxymethylimidazole, 2.10 g of iron powder, 4.25 mL of glacial acetic acid, and 200 mL of methanol wa6 refluxed for 5 hours.
After cooling, the solvent wa~ removed in vacuo, and the re6idue wa6 dis601ved in etbyl acetate. The precipitated iron 6alt6 were removed by filtration through Celite~, and the re6ulting 601ution was wa6hed with water and brine, dried over anhydrous sodium sulfate and concentrated. Column chromatograp~y 1 on 6ilica gel (elution: 10-30S ethyl acetate/benzene) furni6hed 2.95 g of 1-12'-aminobiphenyl-4-yl)methyl~-2-butyl-4-chloro-S-methoxymethylimidazole: NMR (200 MHz, CDC13): ~ 7.43 (d, 2H): 7.19-7.04 (m, 4H):
6.80 (m, 2H); S.l9 (8, 2H); 4.33 (8, 2H); 3.70 (br 8, lH); 3.28 (8, 3H); 2.59 (t, 2H); 1.67 (quint., 2H);
1.34 (6ext., 2H); 0.87 (t, 3H).
PART B: Preparation of l-t2'-Trifluoromethane6ul-fonamidobiphenyl-4-yl)methyl~-2-butyl-4-chloro-5-methoxYmethylimidazole To a solution of 2.95 g of 1-t(2'-aminobiphenyl-4-yl)methyl1-2-butyl-4-chloro-5-methoxymethylimidazole and 1.07 mL of triethylamine in 30 mL of methylene chloride at -78 wa6 added 2.59 mL of trifluoro-methane6ulfonic anhydride dropwise at such rate that the reaction temperature remain6 below -50. ~ol-lowing the addition, the reaction mixture wa6 allowed to warm 610wly to 25. At the point the mixture wa6 poured into dilute aqueous acetic acid. The resulting 6u~pension wa6 6tirred vigorou61y for several minutes and then extracted with methylene chloride. The combined organic pha6e6 were wa6hed with water and brine, dried over anhydrou6 60dium 6ulfate, filtered and concentrated. Column chromatography on silica gel (elution: 20-50% ethyl acetate/benzene) afforded 0.80 g of l-t(2~-trifluoromethane6ulfonamidobiphenyl-4-yl)-methyl]-2-butyl-4-chloro-5-methoxymethylimidazole, m.p. 148-150: NMR (200 MHz, CDC13): ~ 7.60 (d, lH): 7.44-7.27 (m, 5H): 7.07 (d, 2H): 5.20 (6, 2H):
4.29 (6, 2H): 3.27 (8, 3H): 2.57 (t, 2H): 1.65 (quint., 2H): 1.35 (6ext., 2H): 0.88 (t, 3H).
Example6 142 to 147 can or could be prepared by the procedure6 described in Example 141 u6ing the appropriate 6tarting material.
Table 8 N ~
S R6~N~R8 ~--R13 Ex No. R R R R MP(C) NHso2cF3 142 n-butyl H CH2OCH3 4 ~
143 n-~exyl Cl CH20CH3 4 ~
NHso2cF3 144 n-butyl Cl CH20H 4 ~ 171-172 145 FCH2CH2CH2CH2- Cl CH20H 4 ~
NHso2cF3 146 H02CCH2CH2CH2CH2- Cl CH20H 4 ~
NHso2cF3 3 2 2 2 Cl CH20H 4 186 1 3340~
Example 148 PART A: Preparation of 2-Butyl-l-t(2'-carbomethoxy-biphenyl-4-yl)methyl~-4-chloro-5-(chloro-methyl)imidazole-HCl salt 2-Butyl-1-~(2'-carbomethoxybiphenyl-4-yl)methyl]-4-chloro-5-(chloromethyl)imidazole-HC1 6alt va6 pre-pared from 2-butyl-1-~(2'-carbomethoxybiphenyl-4-yl)-methyl~-4-chloro-5-(hydroxymethyl)imidazole u6ing the procedure of Example 1, Part B: m.p. 156.0-161Ø
(200 ~Hz, CDC13) ~ 7.90 ~d, lH, 7Hz); 7.56 (t, lH, J= 7Hz); 7.45 (t, lH, J= 7Hz); 7.43-7.26 (m, 3H);
7.12 (d, 2H, J= 8Hz); 5.47 (6, 2H): 4.48 (6, 2H); 3.70 (s, 3H): 3.14 (t, 2H, J= 7Hz); 1.80 (t of t, 2H, J.
7,7Hz); 1.44 (t of q, 2H, J~ 7,7Hz); 0.92 (t, 3H, J~
7Hz). Anal. . 23 24 2 2 2 H, 5.39; N, 5.99. Found: C, 58.80; H, 5.48; N, 5.69.
Mas6 Calcd. for C23H24C12N202: 430.1215. Pound 430.1215.
PART B: Preparation of 5-Azidomethyl-2-n-butyl-1-~(2~-carbomethoxybiphenyl-4-yl)methyl~-4-chloroimidazole 2-Butyl-l-t(2'-carbomethoxybiphenyl-4-yl)methyl]-4-chloro-5-(chloromethyl)imidazole-HC1 salt (3.31 g, 7.67 mmol, 1 eq), 60dium azide (1.50 g, 23.0 mmol, 3 eq) and DMS0 (100 mL) were mixed and stirred over-night. Water wa6 then added (500 mL) and the aqueou6 extracted with ethyl acetate (3 ~ 300 mL). Tbe organic layer6 were dried (MgS04) and concentrated to yield 3.48 g of product a6 an oil. NMR (200 MHz, CDC13) ~ 7.85 (d, lH, J= 7Hz): 7.54 (t, lH, J= 7Hz);
7.40 (t, lH, J= 7Hz); 7.28 (d, 2H, J- 8Hz); 7.00 (d, 2H, J= 8Hz); 5.20 (6, 2H); 4.23 (8, 2H): 3.67 (8, 3H);
2.63 (t, 2H, J= 7Hz); 1.73 (t of t, 2H, J= 7,7Hz);
-1.39 (t of q, 2H, J= 7,7Hz): 0.91 (t, 3H, J= 7Hz).
Mass Calcd. for C23H24ClN5O2: 438.1697. Pound:
438.1669.
PART C: Preparation of 5-Aminomethyl-2-butyl-l-t(2'-carbomethoxybiphenyl-4-yl)methyl]-4-chloroimidazole 5-Azidomethyl-2-butyl-1-t(2'-carbomethoxybi-phenyl-4-yl)methyl]-4-chloroimidazole (3.48 g) was hydrogenated at 1 atm in methanol (100 mL) over 10%
palladium/carbon (0.5 q). After 1 ~our, the mixture was filtered through Celite~ and the solvent removea in vacuo to give product (2.80 q) a6 an oil. NMR (200 MHz, CDC13) ~ 7.84 (d, lH, J. 7Hz); 7.52 (t, lH, J= 7Hz): 7.40 (t, lH, J= 7Hz); 7.30 (d, lH, J- 7Hz);
7.26 (d, 2H, J= 8Hz): 7.02 td, 2H, Jz 8Hz): 5.27 (6, 2H); 3.74 (6, 2H); 3.65 (6, 3H); 2.60 (t, 2B, J. 7Hz);
1.67 (t of t, 2H, J= 7,7Hz); 1.36 (t of q, 2H, J.
7,7Hz): 0.86 (t, 3H, J= 7Hz). Anal. Calcd. for C23H26ClN3O2-(DMSO)o 5: C, 63.91: H, 6.48:
N, 9.32. ~ound: C, 63.78: H, 6.30: N, 9.14 PART D: Preparation of 5-Aminomethyl-2-butyl-1-[(2~-carboxybiphenyl-4-yl)methyl]-4-chloroimidazole 5-Aminomethyl-2-butyl-1-t(2'-carbomethoxybi-phenyl-4-yl)methyl]-4-chloroimidazole (1.64 g. 3.98 Dmol, 1 eq), O.5N KOH in ~ethanol (11.96 ~L, 5.98 mmol, 1.5 eq), water (1.0 mL) and methanol (20 mL) were mixed and refluxed under N2 overniqht. The 601ution wa~ then brought to neutrality with lN HCl and the 601vent6 removed in vacuo. The re6idue wa6 ta~en up in DM~ and the salt6 filtered off. T~e DMF
was then removed in vacuo to yield 1.76 g of a glass.
NMR (200 MHz, DMSO-d6) ~ 7.50 (d, lH, J= 7Hz):
lB7 1 33409~ -7.40-7.18 (m, 5H); 6.92 (d, 2H, J= 8Hz): 6.50 (bm, 3H); 5.26 (~, 2H); 3.60 (6, 2H); 2.55 (t, 2H, J= 7Hz);
1.51 (t of t, 2H, J= 7,7Hz); 1.27 (t of q, 2H, J=
7,7Hz); 0.81 (t, 3H, J= 7Hz).
PART E: Preparation of 2-Butyl-l-t(2'-carboxybi-phenyl-4-yl)methyl]-4-chloro-5-(ethoxy-carbonYlaminomethyl)imida2ole 2-Butyl-l-t(2'-carboYybip~enyl-4-yl)methyl]-4-chloro-5-(ethoxycarbonylaminomethyl)imidazole wa6 prepared from 5-aminomethyl-2-n-butyl-1-t(2~-carboxy-biphenyl-4-yl)methyl]-4-chloroimidazole u6ing ethyl chloroformate and the Schotten-Baumann procedure described in Example 209, Part B: m.p. 144.0-147Ø
1 NMR (200 MHz, DMS0-d6) ~ 12.74 (8, lH): 7.73 (d, lH, J= 7Hz); 7.63-7.27 (m, SH): 7.03 (d, 2H, J= lOHz):
5.27 (6, 2H); 4.60 (bd, 2H, J= 7Hz): 3.90 (q, 2H, J=
7Hz): 3.34 (6, 2H): 2.47 (t, 2H, J= 7Hz): 1.48 (t of t, 2H, J= 7,7Hz): 1.24 (t of q, 2H, J= 7,7Hz): 1.06 (t, 3H, J= 7Hz): 0.78 (t, 3H, J=7Hz). Anal. Calcd.
25 28ClN304-(H2o)o 33: C, 63.17; H, 6.06;
N, 8.83. Found: C, 63.30: H, 6.35: N, 8.44.
Example6 149-159 in Table 9 were prepared or could be prepared u6ing the appropriate chloroformate by the procedure de6cribed in Example 148, Part6 D and E (the order of which may be interchanged by one 6killed in the art) i.e., 6tarting with the amino e6ter from Part C, reacting it with a chloroformate under Schotten-Baumann type condition6 followed by hydrolyzing the e6ter if nece66ary.
Table 9 1 334092 N ~ 0 R6 ~ N ~ NHCOR
~ ~13 No. _ R _ R MP(C) 149 n-butyl Cl C6H5 C02H 198.0-200.0 150 n-butyl Cl CH3 CO2H 151.0-155.0 151 n-butyl Cl CH2CH2CH3 C02H 115.5-117.0 1 152 n-butyl Cl CH2(CH3)2 C02H 135.5-138.0 153 n-butyl Cl CH2CH2CH2CH3 C02H 123.0-125.0 154 n-butyl Cl l-adamantylC02H 170.0-172.0 155 n-propyl Cl CH3 C02H
156 n-butyl Cl CH3 ~ ~ 202.0-204.5 N-N
157 n-butyl Cl (CH2)2cH3 ~ N~N
N-N
158 n-propyl Cl CH3 ~ N,N
H
N-N
159 n-propyl H 2 3 ~ N,N
Examples 160-164 in Table 10 were prepared or could be prepared from 2-n-butyl-1-t(2'-carbomethoxybi-phenyl-4-yl)methyl]-S-chloro-4-(hydroxymethYl)imidazole using the procedures in Example 148.
Table 10 N ~ NHCO~
~6 ~ N ~ a8 ~
Ex 15 No. R6 R R R NP(C) 160 n-butyl Cl CH3 COOH 200-205 161 n-butyl 2 3 COOH
162 n-butyl Cl CH2CH2CH3 COOH 166.5-169.5 163 n-butyl Cl CH2CH2CH2CH3 COOH
164 n-butyl Cl CH(CH3)2 COOH
191 1 3340q2 PART A: Preparation of 2-n-Butyl-l-t(2'-carbomethoxy-biphenyl-4-yl)methyl]-4-chloro-5-(1-naphthyl-aminocarbonylaminomethyl)imidazole 5-Aminomethyl-2-butyl-1-t(2'-carbomet~oXybi-phenyl-4-yl)methyl)-4-chloroimidazole (1.00 g, 2.4 mmol, 1 e~) and l-napht~yl ~60cyanate (0.35 mL, 2.4 mmol, 1 eq), were mixed and ~tirre~ ~n c~loroform at room temperature for 3 day6. The 601vent wa~ removed in vacuo and the re6idue wa6 purified by flas~
chromatoqraphy over 6ilica gel in 1:1 ~exane/ethyl acetate to yield 770 mg of a white gla6s. NMR (200 MHz, CDC13) ~ 7.83 (d, 3H, J~ 6Hz): 7.67 (d, lH, J= 6Hz): 7.56-7.18 (m, 9H): 6.97 (d, 2H, J~ 7Hz): 6.74 (6, lH): 5.27 (6, 2H); 4.74 (6, lH): 4.39 (d, 2H, J=
7Hz): 3.58 (6, 3H); 2.60 (t, 2H, J= 7Hz): 1.43-1.21 (m, 4H): 0.85 (t, 3H, J= 7Hz).
PART B: Preparation of 2-n-Butyl-1-~(2~-carboxy-biphenyl-4-yl)methyl]-4-chloro-5-(1-naphthylaminocarbonylaminomethyl)-imidazole The title compound wa6 prepared from 2-n-butyl-1-t(2'-carbomethoxybiphenyl-4-yl)methyl]-4-chloro-5-(1-naphthylaminocarbonylaminomethyl)imidazole by the hydroly6i6 procedure de6cribed in Example 148, Part D. Work-up yielded 380 mg of white cry6talline 601id:
m.p. 169-175. NMR (200 MHz, DMSO-d6) ~ 8.45 (6, lH): 8.05-7.03 (m, 15H): 6.97 (6, lH): 5.34 (6, 2H):
4.30 (d, 2H, J= 5Hz): 2.52 (t, 2H, J= 7Hz): 1.48 (t of t, 2H, J= 7,7Hz): 1.21 (t of q, 2H, J= 7,7Hz): 0.85 (t, 3H, J= 7Hz). Anal. Calcd. for 33 31ClN43-(H2)0 5: C, 68.77 H
5.60; N, 9.70. Found: C, 68.88: H, 5.67; N, 9.70.
Examples 166-172 in Table 11 were prepared or could be prepared using the appropriate isocyanate by the procedure described in Example 165.
Ta~le 11 ~33409 ~
1 ~,H " H
R6 N 2~-C-N-R
~;
No R Cl CH3 C02H ~p(oC~
167 n-Bu Cl CH2 3 co2H
168 n-Bu Cl CH2cH2cH3 C0 H
169 n-Bu Cl CH2CH2CH2cH3C2H
170 n-Bu Cl CH(cH3~2 C0 H
171 ~-Bu Cl ~ co2n 163-166 172 n-Bu Cl l-adamantyl~ ,N
-194 l 3340q ~
ExamPle 173 Preparation of 2-n-Butyl-4-chloro-5-methoxymethyl-l-t(2'-((tetrazol-5-yl)aminocarbonyl)biphenyl-4-yl)-methyl~imidazole 2-n-Butyl-l-t(2'-carboxybiphenyl-4-yl)methyl]-4-chloro-5-(methoYymethyl)imidazole tl- g) wa6 fir6t converted to the corre~ponding acid chloride and then coupled to 5-aminotetrazole by the procedure in Example 78, Part C to yield 0.87 g of a yellow gla66.
Fla~h chromatography in 100% ethyl acetate over 6ilica qel yielded 77.1 mq of a white 601id: m.p. 169-173.
NMR (200 MHz, CDC13, DMS0-d6) ~ 12.0 (br 6, lH):
7.73-7.30 (m, 6H): 7.00 (d, 2H, J= 7Hz): 5.18 (6, 2H):
4.23 (6, 2H): 2.55 (t, 2H, Js 7Hz) 1.63 (t of t, 2H, J= 7,7Hz): 1.31 (t of q, 2H, J. 7,7Hz): 0.84 (t, 3H, J= 7Hz). Anal. Calcd. for C24H26ClN702-(H20)2:
C, 55.87; H, 5.86. Found: C, 56.01; H, 6.01.
Example 174 PART A: Preparation of 2-n-Butyl-4-chloro-1-~(2'-(hydroxymethyl)biphenyl-4-yl)methyl]-5-(methoxYmethyl)imidazole 2-n-Butyl~ 2'-carbomethoxybiphenyl-4-yl)-methyl]4-chloro-5-(methoxymethyl)imidazole l5.62 g, 13 mmol, 1 eq) wa6 di6601ved in TH~ (50 mL) and to it wa6 610wly added a lM lithium aluminum hydride 601ution in THF (39.5 mL, 39 mmol, 3 eq). The re6ultant mixture wa6 refluxed under N for 2 bours and wor~ed up according to Fie6er and Pie6er, V.l, p. 584 (Steinhardt procedure) to yield 4.68 q of a ligbt yellow oil which 610wly cry~tallized. NMR (200 HHz, CDC13) ~ 7.57 (bd, lH, J= 7Hz): 7.47-7.20 (m, 5H):
7.03 (d, 2H, J= 9Hz); 5.18 (8, 2H); 4.58 (6, 2H): 4.32 (6, 2H); 3.28 (6, 3H); 2.60 (t, 2H, J. 7Hz); 1.67 (t of t, 2H, J= 7, 7Hz); 1.35 (t of q, 2H, J. 7,7Hz):
0.86 (t, 3H, J= 7Hz). Anal. Calcd. for C23H27ClN2O2:
C, 69.25: H, 6.82: Cl, 8.89. Found: C, 69.42; H, 6.87; Cl, 8.65.
PART B: Preparation of 2-n-Butyl-4-chloro-1-t(2~-(cyanomethyl)biphenyl-4-yl)methyl~-5-(methoxymethYl~imidazole 2-n-Butyl-4-chloro-1-t(2'-(hydroxymethyl)-biphenyl-4-yl)methyl-5-(methoxymethyl)imidazole (4.68 g) wa6 converted to the title cyanomethyl compound by the procedure de6cribed in Example 1, Part B. Work up yielded 5.20 g of a brown oil which wa6 further reacted with purification. NMR (200 HHz, CDC13) ~
7.54 (m, lH); 7.40 (m, 2H); 7.28 (m, 3H); 7.08 (d, 2H, J= lOHz); 5.23 (6, 2H); 4.33 (s, 2H); 3.63 (6, 2H);
3.30 (6, 3H); 2.60 (t, 2H, J= 7Hz): 1.70 (t of t, 2H, J= 7,7Hz); 1.37 (t of q, 2H, J= 7,7Hz); 0.90 (t, 3H, J= 7Hz). Ma66 Calcd. for C24H26ClN30:
407.1764. Found: 407.1778.
196 l 334092 PART C: Preparation of 2-n-Butyl-4-chloro-5-methoxy-methyl-l-[(2'-((tetrazol-5-yl)methyl)bi-phenyl-4-Yl)methyl]imidazole 2-n-Butyl-4-chloro-1-t(2'-(cyanomethyl)biphenyl-4-yl)methyl~-5-(methoxymethyl)imidazole (5.20 g) was converted to the above tetrazole in 2 days usinq the procedure of Example 90, Part C. Wor~-up and fla6h chromatography over silica gel eluting with a gradient solvent sy6tem of 1:1 hexane~ethyl acetate to 1:1 ethyl acetate/i60propanol yielded 3.13 g of a light yellow ~olid; m.p. 149.0-152.5. NMR (200 MHz, CDC13) ~ 7.37-7.15 (m, 6H): 6.96 (d, 2H, Jz 9Hz):
5.18 (6. 2H); 4.30 (fi, 2H): 4.24 (6, 2H): 3.27 (8, 3H): 2.57 (t, 2H, J5 7Hz); 1.56 (t of t, 2H, J-1 7,7Hz); 1.28 (t of 9, 2H, J= 7,7Hz): 0.77 (t, 3H, J=
7Hz). Anal. Calcd. for C24H27ClN60: C, 63.97, H, 6.03: Cl, 7.86. Pound: C, 63.79: H, 6.04: Cl, 7.70.
ExamPle 175 20Preparation of 2-n-Butyl-l-t(2l-(carboxymethyl)bi-phenyl-4-yl)methyl]-4-chloro-5-(hydroxymethyl)-imidazole-dicyclohexylamine 6alt 2-n-Butyl-4-chloro-1-1(2'-(cyanomethyl)biphenyl-4-yl)methyl~-5-(metboxymethyl)imidazole (2.60 g) and a 1:1 mixture of concentrated aqueous HCl and glacial acetic acid (50 mL) were mixed together and then refluxed for 6 hour6. The 601vent6 were removed in vacuo and water (200 mL) wa6 added to the re6idue.
The pH was adju6ted to 3 with concentrated NH40H and this aqueous mixture was eYtracted with etbyl acetate (3 x 200 mL). The organic layers were combined, dried (MgS04) and the 601vent removed in vacuo to yield an oil. Subseguent flash chromatography in 60:40 ethyl 3 acetate/hexane to 100% isopropanol yielded 1.07 g of a glass. This product was dissolved in acetone and dicyclohexylamine was added (1 eq). A gum precipitated which was redi~olved with more acetone (total of 75 mL) and heat. Upon cooling, 601id precipitate was obtained (291 mg); m.p. 135.0-137Ø
NMR ~hows -OCH3 to be mis~ing. NMR (200 MHz, CDC13) ~ 7.43-7.13 (m, 6H); 6.95 (d, 2H, J. 8Hz);
5.20 (6, 2H) 4.46 (6, 2H); 3.45 (6, 2H); 2.76 (m, 2H);
2.60 (t, 2H, J= 7Hz); 2.00-1.03 (m, 24H); 0.87 (t, 3H, J= 7Hz). Mas6 Calcd. for C23H25ClN203:
412 1554. ~ound: 412.1544.
~xample 176 PART A: Preparation of 2-n-Butyl-4-chloro-1-t(2~-(hydrazido)biphenyl-4-yl)met~yl]-5-(methoxy-lS methYl)imidazole 2-~-Butyl-1-~(2'-carbomethoxybiphenyl-4-yl)-methyl]-4-chloro-5-(methoxymet~yl)imidazole (2.00 g, 4.7 mmol, 1 eq), hydrazine (1.5 mL, 46.8 mmol, 10 eq) and methanol (30 mL) were mixed together and then refluxed for 3 days after which 1.5 mL more of hydrazine was added and the reaction refluxed for another day. More hydrazine (1.5 mL) wa6 again added and the reaction was refluxed for an additional day.
The reaction wa6 worked up by fir6t removing the hydrazine and methanol in vacuo, following by taking up the residue in ethyl acetate (200 mL) and wa6hing it with water (3 x 100 mL). The organic layer wa6 dried (MgS04) and the 601vent removed in vacuo to yield 1.37 g of a white gla66. NMR (CDC13, 200 MHz,) ~ 7.67-7.31 (m, 4H); 7.40 (d, 2H, JS 9Hz):
7.03 (d, 2H, J= 9Hz); 7.56 (b6, lH): 5.17 (6, 2H):
4.27 (~, 2H); 3.25 (~, 3H); 2.57 (t, 2H, J= 7Hz); 1.70 (t of t, 2H, 7,7Hz); 1.34 (t of q, 2H), J= 7,7Hz);
0.86 (t, 3H, J= 7Hz). Anal. Calcd. for C23H27ClN402:
1 3340~2 C, 64.70; H, 6.37; N, 13.12. Found: C, 64.47; H, 6.35; N, 12.85.
PART B: Preparation of 2-n-Butyl-4-chloro-5-methoxy-methyl-l-t4-(2-(trifluoromethyl6ulfonylhydra-zido~biPhenyl-4-yl)methyllimidazole A ~olution of triflic anhydride (0.42 mL, 2.5 mmol, 1.5 eq) in methylene chloride (2 mL) was slowly dripped into a ~tirred ~olution at -78C of 2-n-butyl-4-chloro-1-t(2'-(hydrazido)biphenyl-4-yl)methyl]-5-(methoxymethyl)imidazole (0.71 g, 1.7 mmol, 1.0 eq) and triethylamine (0.35 mL, 2.5 mmol, 1.5 eq) in methylene chloride (5 mL). The 601ution wa~ 6tirred at -78C for 1 ~our and the~ allowed to warm to room temperature. After 2 hour6 at room temperature, water (100 mL) was added, the pH adju~ted to 5 and the aqueou~ layer extracted with ethyl acetate (3 x 100 mL). The organic layerE were dried (MgS04), the 601vent removed in vacuo, and the residue fla~h chromatographed over 6ilica gel beginning in 1:1 hexane/ethyl acetate and fini6hing in 100% ethyl acetate to yield 380 mg of a light yellow gla~6. NMR
(200 MHz, CDC13) ~ 7.82-7.15 (m, 8H): 6.94 (d, 2H, J= 8Hz): 5.13 (s, 2H): 4.25 (~, 2H): 3.17 (~, 3H):
2.53 (t, 2H, J= 7Hz): 1.69 (t of t, 2H, J= 7,7Hz):
1.27 (t of q, 2H, J= 7,7Hz): 0.81 (t, 3H, J= 7Hz).
Fast Atom Bombardment MaE~ Spectrum: Ma~ Calcd. for C24H26ClF3N4045: 559.15. Found: 559.12.
Example 177 PART A: Preparation of 4'-Methylbiphenyl-2-carboxalde-hyde Methyl 4~-methylbiphenyl-2-carboxylate (20.00 g, 88 mmol, 1 eq) was di6601ved in dry toluene (250 mL) 1 3340~2 and cooled to -78: Diisobutylaluminum hydride (1.0 M
in toluene, 220.0 mL, 220 mmol, 2.2 eq) wa6 then dripped in 610wly over 25 minute6 keeping the temperature under -70. When the addition was complete, the mixture waE 6tirred at -78 for 15 minutes and then methanol (10 mL) wa6 added cautiously. ~en ga6 evolution was complete, the mixture was poured into a 601ution of Rochelle 6alt (100 mL of saturated solution plus 600 mL water). The mixture was stirred or 6ha~en until an extractable solution was obtained. The layer6 were 6eparated and the aqueous layer extracted with ether (2 x 200 mL).
The organic layers were combined, dried (MgSO4) and the solvent removed in vacuo to yield 16.7 q of a light yellow oil. NMR (200 MHz, CDC13) ~
7.56-7.16 (m, 8H); 4.59 (s, 2H); 2.40 (s, 3H); 1.74 (6, lH). This oil (16.7 g, 84 mmol, 1 eg) was 6ubsequently oxidized by di6solving in methylene chloride (100 mL) and stirring with manganese dioxide (7 34 g~ 84 mmol, 1 eq). After 6tirring for one day at room temperature, more manganese dioxide (14.68 g, 168 mmol, 2 eq) was added. The next day, 14.68 g more of manganese dioxide was again added. After another day of stirring, the reaction was filtered through Celite~ and the filtrate evaporated to an oil. The oil was chromatographed in 9:1 hexane/ethyl acetate over silica gel to yield 13.4 g of a light yellow opaque oil. The above oxidation can also be performed using pyridinium chlorochromate. NMR (CDC13, 200 MHz) ~ 9.98 (s, lH); 8.01 (d, lH, J= 7Hz); 7.64 (t, lH, J= 7Hz); 7.53-7.38 (m, 2H); 7.28-7.17 (m, 4H);
2.43 (s, 3H). Mass Calcd. for C14H120: 196.0888.
Found: 196.0881.
200 ~ 3340~2 PART B: Preparation of 4~-Methyl-2-(2-nitroethen Yl)biphenyl 4'-Methylbiphenyl-2-carboxaldehyde (13.~1 g, 67.3 mmol (1.0 eq), nitromethane (4.74 mL, 87.5 mmol, 1.3 eq), ammonium acetate (2.07 g, 26.0 mmol, 0.4 eq) and glacial acetic acid (30 mL) were mixed and refluxed for 2 day6, at which time more nitromethane (4.74 mL) and ammonium acetate (2.07 g) were added and the reaction was refluxed for an additional 5 hours.
The reaction mixture was poured into ice water (300 mL) and extracted with ethyl acetate (300 mL). The ethyl acetate layer was wa6hed with water (3 x 200 mL), the organic layer dried (~gS04), the 601vent removed iD vacuo and the re~idue chromatographed in 1:1 hexane/toluene to yield 11.22 g of a light yellow oil which cry6tallized. The product was recry6tallized from methylcyclohexane to yield 8.47 g of yellow cry6tals: m.p. 64.0-65Ø NMR (200 MHz, CDC13) ~ 8.04 (d, lH, J= 13Hz): 7.69 (d, lH, J=
9Hz) 7.59-7.37 (m, 4H): 7.50 (d, lH, Jz 13 Hz): 7.27 (d, 2H, J= 7Hz): 7.19 (d, 2H, J= 7Hz): 2.41 (6, 3H).
Anal. Calcd. for C15H13N02: C, 75.30: H, 5.48;
N, 5.85. Found: C, 75.32: H, 5.56: N, 5.5B.
PART C: Preparation of 4'-methyl-2-(1,2,3-triazol-4-yl)biPhenyl 4'-Methyl-2-(2-nitroethen-1-yl)biphenyl (6.58 g, 27.5 mmol, 1 eg), 60dium azide (5.40 g, 82.3 mmol, 3 eq), and dimethyl6ulfoxide (minimum to di~601ve everything) were mixed together and ~tirred at room temperature for 4.5 hours. Ethyl acetate (500 mL) was then added and the organic phase washed with water (3 x 400 mL). T~e organic layer wa~ dried (MgS04) and the solvent removed in vacuo to yield 6.54 g of an 201 1 3340~2 orange glass. Chromatography in 75:25 hexane~ethyl acetate yielded 2.87 g of of a yellow glass. NMR (200 MHz, CDC13) ~ 7.83 (m, lH); 7.51-7.32 (m, 3H);
7.18 (d, 2H, J= BHz); 7.13 (d, 2H, J= 8Hz): 7.03 (s, lH); 2.38 (~, 3H). Mass Calcd. for C15H13N3:
235.1110. Found: 235.1111.
PART D: Preparation of 4'-Methyl-2-(N-(trip~enyl-methyl)-1~2~3-triazol-4-yl)biphenYl 4'-Methyl-2-(1,2,3-triazol-4-yl)biphenyl (2.61 g, 11 mmol, 1.0 eq), triethylamine (1.69 mL, 12 mmol, 1 eq), tritylbromide ~3.88 g, 12 mmol, 1 eq) and methylene chloride (30 mL) were mixed and ~tirred at 0C and then allowed to warm to room temperature.
After 1 hour, ethyl acetate was added (200 mL) and the organic phase was washed with water (3 x 200 mL). The organic layer was dried (MgS04) and the solvent removed in vacuo to yield S.lS g of a yellow ~olid.
This product was recrystallized from methylcyclohexane to give 3.26 9 of off-white crystal~; m.p.
181.0-182.5. NMR (200 MHz, CDC13) ~ 8.18 (d, lH, J= 7Hz): 7.50-7.16 (m, 12H); 7.05-6.89 (m, 10 Hz);
6.47 (6 , lH); 2.54 (~, 3H). Anal. Calcd. for C34H27N3: C, 85.50; H, 5.70; N, 8.80. Found:
C, 86.60; H, 5.80; N, 8.94.
PART E: Preparation of 2-n-Butyl-4-chloro-5-hydroxymethyl-l-[(2'-(N-(triphenylmethyl)-1,2,3-triazol-4-yl)biphenyl-4-yl)methyl~-imidazole 4'-Methyl-2-(N-(triphenylmethyl)-1,2,3-triazol-4-yl)biphenyl (3.14 g, 6.57 mmole6) was brominated in the benzylic position by the procedure in Example 85, Part B, using benzoylperoxide in~tead of AIBN as radical initiator. Filtration of succinimide and evaporation yielded 4.45 g of a crude oil which was used as is.
NMR (200 MHz, CDC13) ~ CH2Br, 4.41. Thi6 bromide (4.33 g, approx. 7.8 mmol, 1 eq) wa6 alkylated onto 2-n-butyl-4-chloro-5-(hydroxymethyl)imidazole by the procedure de6cribed in ~xample 1, Part A. Fla6h chromatography in 75:Z5 hexane~ethyl acetate over 6ilica gel yielded a yellow 601id (0.67 g) which wa6 recry~tallized from carbon tetrachloride to yield 447 mg of white cry6tal6: m.p. 173.0-176.5. NMR
(CDC13, 200 MHz) ~ 8.03 (d, lH, J- 9Hz): 7.51-7.14 (m, 14H); 6.98 (m, 6H): 6.86 (d, 2H, J~ 9Hz): 6.63 (6, lH); 5.15 (6, 2H): 4.33 (6, 2H): 2.53 (t, 2H, J~ 7Hz):
1.15 (t of t, 2H, J= 7,7Hz): 1.32 (t of g, 2H, J5 7,7Hz): 0.87 (t, 3H, J= 7Hz). Ha66 Calcd. for C42H38ClN50: 663.2765. Pound: 663.2762.
PART P: Preparation of 2-n-Butyl-4-chloro-5-hydroxy-methyl-l-[(2'-1,2,3-triazol-4-yl)biphenyl-4-yl)methYl~imidazole 2-n-Butyl-4-chloro-5-hydroxymethyl-1-t(2'-(N-(triphenylmethyl)triazol-4-yl)biphenyl-4-yl)methyl]-imidazole (408 mq, 0.6 mmol, 1 eq), 1,4-dioxane (5 mL), water (1 mL) and 4.0 N HCl in dioxane (0.46 mL, 1.8 mmol, 3 eq) were mixed and ~tirred at room temperature. After 2 hours, water wa6 added (200 mL), and the aqueou6 layer extracted with ethyl acetate (3 x 200 mL). The organic layer6 were dried (MgS04) and the 601vent removed in vacuo to yield 260 mg of an off-white gla66. Pla6h chromatography of the product in 100% ethyl acetate over 6ilica gel yielded 140 mg of a white gla66. NMR (200 MHz, CDC13) ~ 7.82 (m, lH): 7.50-7.25 (m, 3H): 7.17 (d, 2H, J= 9Hz): 6.98 (d, 2H, J= 9HZ); 6.95 (6, lH); 5.23 (6, 2H): 4.52 t6. 2H):
2.58 (t, 2H, J= 7Hz): 1.63 (t of t, 2H, J- 7,7Hz):
1.30 (t of q, 2H, J= 7,7Hz): 0.82 (t, 3H, J= 7Hz).
Ma6s Calcd. for C23H24ClN50: 421.1669. Pound:
421.1670.
-ExamPles 178 and 179 PART A: Preparation of Ethyl 3-(4-methylphenyl)-3-oxo-2-(al 1Y1 ) PrOPanOate Ethyl 3-(4-met~ylphenyi)-3-oxopropanoate (prepared as de6cribed in W. Wierenga and H. I.
Skulnick, J. Orq. Chem. (1979), 44, 310) (63.66 g, 309 mmol, 1 eq) wa6 added to a fre6hly prepared 60dium ethoxide 601ution (Na, 7.43 g, 323 ~mol, 1.05 eg:
EtOH, 250 mL). The ethanol wa6 remoYed 1n ~acuo and the re6idue wa6 di6601ved in DMF (250 mL). Allyl bromide (29.3 mL, 338 mmol, 1.1 eq) followed by 60dium iodide (4.56 g, 304 mmol, 1 eq) vere then added and the content6 ~tirred overnight at room temperature.
The DMF wa6 removed in vacuo, water (250 mL) wa6 added and tbe aqueous layer extracted with ethyl acetate (3 x 200 mL). The organic layer6 were dried (MgSO4) and the 601vent removed in vacuo to yield 74.21 g of an amber oil. NMR (200 MHz, CDC13) ~ 7.81 (d, 2H, J= 10Hz): 7.30 (d, 2H, J= 10 Hz); 5.96-5.72 (m, lH):
2 5.21-5.00 (m, 2H): 4.41 (t, lH, J= 7Hz): 4.16 (q, 2H, J= 7Hz): 2.78 (t, 2H, J= 7Hz): 2.42 (8, 3H): 1.18 (t, 3H, J= 7Hz). Anal. Calcd. for C15H18O3: C, - 73.15: H, 7.37. Eound: C, 73.10: H, 7.38.
PART B: Preparation of 3-Carboethoxy-4-(4-methyl-phenyl)-4-(oxo~butanal Ethyl 3-(4-methylphenyl)-3-oxo-2-(allyl)-propanoate (74.21 g, 301 mmol, 1.0 eq), 06mium tetroxide (100 mg, cat.), 60dium metaperiodate (141.8 g, 663 mmol, 2.2 eq), etber (500 mL) and water (1 L) were mixed and 6tirred at room temperature.
After 24 hour6, an additional 110 mg of O6O4 wa6 added and after another 24 hour6, 200 mg more of 204 1 3340~2 O~O4 was added together with 60dium metaperiodate (190 g, 888 mmol, 3.0 eq). After 4 day6, the layer6 were 6eparated and the ether layer wa6hed with aqueou6 60dium bi6ulfite (1 Y 500 mL) followed by brine (1 x 300 mL). The ether layer wa6 dried (HgSO4) and the 601vent removed in vacuo to yield 64.99 g of a dark brown oil. Thi~ oil wa6 fla6h chromatographed over 6ilica gel in 4:1 hexane/ethyl acetate to yield 37.5 g of an amber oil. NMR (200 MHz, CDC13) ~ 9.79 (s, lH): 7.93 (d, 2H, J= 9Hz): 7.27 (d, 2H, J- 9Hz): 4.87 (t, lH, J= 7Hz): 4.13 (q, 2H, J= 7Hz): 3.37-3.08 (AB
multiplet, 2H): 2.40 (6, 3H); 1.14 (t, 3H, J= 7Hz).
Anal- Calcd- for C14H164 C~ 67-73; H~ 6-50-~ound: C, 67.53; H, 6.54.
PART C: Preparation of 3-Carboethoxy-2-(4-methyl-Phenyl)furan Ethyl 3-CarboethoYy-4-(4-methylphenyl)-4-(oxo)-butanal (10.00 g), trifluoroacetic anhydride (50 mL) and trifluoroacetic acid (2 drop6) were mixed and 6tirred at 0 over ice and allowed to warm to room temperature. After 3 hour6, more trifluoroacetic anhydride (50 mL) together with trifluoroacetic acid (2 drop6) were added at room temperature. The next day, the 601vent wa6 removed ~n vacuo and the re6idue partitioned between 1 N NaOH (200 mL) and ethyl acetate (200 mL). The layer6 were 6eparated and the orqanic layer wa6hed with 1 N NaOH (2 x 200 mL). The organic layer wa6 dried (HgSO4) and the 601vent removed in vacuo to yield a brown oil (9.95 g) which wa6 fla6h chromatographed in 99:1 hexane~ethyl acetate to yield 2.57 g of an off-white 601id; m.p.
79.0-80.5. NMR (200 MHz, CDC13) ~ 7.88 (d, 2H, J= 9Hz); 7.42 (d, lH, J= 2Hz); 7.26 (d, 2H, J= 9Hz);
-~ 20s 1 334092 6.83 (d, lH, J=2Hz): 4.34 (q, 2H, J= 7Hz); 2.40 (8, 3H); 1.34 (t, 3H, J= 7Hz). Anal. Calcd. for ClgH14O3: C, 73.03; H, 6.13. Found: C, 73.52;
H, 6.30.
PART D: Preparation of 2-n-Butyl-l-t4-(3-carboxyfuran-2-yl)benzyl~-4-chloro-5-(hydroxymethyl)-imidazole (isomer A) and 2-n-butyl-1-t4-(3-carboxyfuran-2-yl)benzyl]-5-chloro-4-(hydroxy-methyl~imidazole (i60mer B~
3-Carboethoxy-2-(4-methylphenyl)furàn was brominated, alkylated, and ~aponified by the procedures described in Example 85, Parts B, C, and E.
I60mer A, the faster eluting ~60mer, was recrystallized from acetonitrile; m.p. 158.5-160Ø
NMR (200 MHz, DMS0-d6) ~ 12.80 (bm, lH); 7.92 (d, 2H, J= 9H): 7.82 (d, lH, J= 2Hz); 7.17 (d, 2H, J5 9Hz); 6.84 (d, lH, J= 2Hz): 5.30 (s, 2H), 5.30 (m, lH); 4.34 (6, 2H); 2.47 (t, 2H, J= 7Hz); 1.47 (t of t, 2H, J = 7,7Hz); 1.24 (t of q, 2H, J= 7,7Hz); 0.74 (t, 3H, J = 7Hz). Anal. Calcd. for C20H21ClN2O4:
C, 61.78; H, 5.44; N, 9.12. Found: C, 61.66; H, 5.39; N, 9.09.
~somer B wa6 recrystallized from nitromethane/
acetonitrile; m.p. 118.5-120.5. NMR (200 ~Hz, DMS0-d6) ~ 12.89 (bm, lH); 7.92 (d, 2H, J= 9Hz);
7.82 (d, lH, J= 2Hz); 7.13 (d, 2H, J= 9Hz); 6.83 (d, lH, J= 2Hz); 5.23 (8, 2H); 4.93 (m, lH) 4.29 (d, 2H, J= 7Hz); 2.57 (t, 2H, J= 7Hz); 1.53 (t of t, 2H, J =
7,7Hz); 1.27 tt of q, 2H, J= 7,7Hz); 0.77 (t, 3H, J=
7Hz). Mass Calcd. f 20 21 2 4 Found: 388.1171.
Example 180 1 3 S 4 0 9 2 PART A: Preparation of l-t(2'-Carbomethoxybiphenyl-4-yl)methyl~-2-butyl-4-chloro-5-(2-metho~y-ethoxYmethoxymethyl~imidazole To a-solution of 7.50 mL of 1.6 M n-butyllithi-um/hexane in 50 mL of tetrahydrofuran at 0 was added dropwi6e 1.50 mL of t-butanol. To this 601ution was added 4.52 g of 1-lt2'-carbomethoYybiphenyl-4-yl)-methyl]-2-butyl-4-chloro-5-hydroxymethylimidazole 1 followed by 1.50 ml of 2-methoxyetho~ymethyl chloride. The re6ulting 601ution wa6 6tirred at 25 for 16 hours. The mixture was diluted with diethyl ether, washed with water and brine, dried over anhydrou6 60dium 6ulfate, filtered and concentrated.
Column chromatoqraphy afforded 3.50 g of l-t(2'-carbomethoxybiphenyl-4-yl)methyl~-2-butyl-4-chloro-5-(2-methoxyethoxymethoxymethyl)imidazole. M~R (200 ~Hz, CDC13) ~ 7.83 (d, lH); 7.52 (t, lH): 7.40 (t, lH), 7.28 (m, 3H): 7.00 (d, lH): 5.19 (6, 2H): 4.68 (6, 2H): 4.48 (6, 2H): 3.67 (m, 2H): 3.64 (6, 3H):
3.54 (m, 2H): 3.37 (6, 3H): 2.58 (t, 2H): 1.67 (quint., 2H): 1.34 (6ext., 2H): 0.88 (t, 3H).
PART B: Preparation of l-t(2'-Carboxybiphenyl-4-yl)-methyl~-2-butyl-4-chloro-5-(2-methoxy-ethoxymethoxymethyl)imidazole A 601ution of 3.15 g of 1-[(2'-carbomethoxy-biphenyl-4-yl)methyl]-2-butyl-4-chloro-5-(2-methoxy-ethoxymethoxymethyl)imidazole and 2.77 g of pota66ium methanethiolate in 125 mL of dimethylformamide was 6tirred at 125 for 4 hour6. After cooling the 601vent was removed in vacuo, and the re~idue was dissolved in water. The resulting aqueou6 601ution was wa~hed with diethyl ether, adjusted to pH 3 207 1 3340~2 employing 10~ hydrochloric acid, and extracted with methylene chloride. The combined organic layer6 were washed with brine, dried over anhydrou6 60dium 6ulfate, filtered, and concentrated. The crude product was recry6tallized from chlorobutane to afford 2.45 g of 1-~(2'-carboxybiphenyl-4-yl)methyl]-2-butyl-4-chloro-5-(2-methoxyethoYymethoxymethyl)-imidazole. NMR (200 HHz, CDC13) ~ 7.95 (d, lH):
7.57 (t, lH): 7.46 (t, lH): 7.38 (m, 3H): 7.05 (d, 2H): 5.22 (8, 2H): 4.64 (6, 2H) 4.48 (6, 2H): 3.58 (m, 4H): 3.40 (6, 3H): 2.54 (t, 2H): 1.60 (guint., 2H): 1.32 (6ext., 2H): 0.84 (t, 3H).
PART C: Preparation of l-t(2'-~ethoxyaminocarbonyl-biphenyl-4-yl)methyl~-2-butyl-4-chloro-5-(2-methoxyethoxYmethoxymethyl)imidazole A 601ution of 0.24 ml of oxalyl chloride in 5 mL
of chloroform wa6 added dropwi6e to a 601ution of 1 mL
of dimethylformamide in 4 mL of chloroform at -20.
After thi6 601ution had been 6tirred at -20 for 20 minutes, 0.2~ mL of N-methylmorpholine wa6 added followed by 1.21 g of 1-[(2'-carboxybiphenyl-4-yl)-methyl]-2-butyl-4-chloro-5-(2-methoxyethoxymethoxy-methyl)imidazole. After another 20 minute6 at -20, 0 55 ml of N-methylmorpholine and 1.35 mL of methoxylamine were added to the mixture. The reaction mixture wa6 warmed 610wly to 25, 6tirred at 25 for 4 hour6, and finally refluxed for 40 hour6. After cooling the mixture wa6 diluted with ethyl acetate.
The re6ulting 601ution wa6 wa6hed with 10~
hydrochloric acid, water, 10% 60dium bicarbonate 601ution and brine. Finally the 601ution wa6 dried over anhydrou6 60dium 6ulfate, filtered, and concentrated in vacuo. Column chromatography (elution: methanol/chloroform) furni6hed 0.21 g of l-t(2'-methoxyaminocarbonylbiphenyl-4-yl)methyl~-2-butyl-g-chloro-5-(2-methoxyethoxymethoxymethyl)-imidazole. NMR (200 MHz, CDC13) ~ 7.85 (6, lH):
7.63 (d, lH); 7.53-7.33 (m, 5H); 7.05 (d, 2H): 5.20 (6, 2H); 4.67 (6, 2H): 4.47 (6, 2H): 3.63 (m, 5H):
3.55 (m, 2H): 3.36 (6, 3H): 2.56 (t, 2H); 1.67 (m, 2H); 1.32 (m, 2H); 0.87 (t, 3~).
PART D: Preparation of l-t(2'-Methoxyaminocarbonyl-biphenyl-4-yl)methyl]-2-butyl-4-chloro-5-hydroxYmethylimidazole A 601ution of 0.20 g of 1-1(2'-methoxyaminocar-bonylbiphenyl-4-yl)methyll-2-butyl-4-chloro-5-(2-methoxyethoxymethoxymethyl)imidazole in 60 ml of 1.5 Maqueou~ tetrafluoroboric acid/acetonitrile wa6 stirred for 20 hour6 at 25. The reaction mixture wa6 poured into dilute 60dium bicarbonate 601ution, and the re6ulting mixture wa6 extracted with diethyl ether.
2 The combined organic pha6e6 were wa6hed with brine, dried over anhydrou6 60dium 6ulfate, filtered, and concentrated. Column chromatography (elution:
methanol/chloroform) provided 0.11 g of l-t(2~-methoxyaminocarbonylbiphenyl-4-yl)methyl]-2-butyl-4-chloro-5-hydroxymethylimidazole. NMR (200 MHz, CDC13) ~ 11.31 (br 6, lH): 7.48 (m, lH); 7.41-7.33 (m, 5H); 7.09 (d, 2H); 5.27 (br 6, 3H); 4.32 (d, 2H);
3.44 (6, 3H); 2.49 (t, 2H); 1.48 (guint., 2H); 1.25 (6ext., 2H); 0.80 (t, 3H).
The following compounds were prepared according to the procedure6 described in the above example.
-NMR (200 MHz, DMSO-d6) Exa~ple 181 ~ 11.29 (br s, lH), N__~Cl 7.48 (m, lH), 7.33 (m, ~ ~ \~ OH lOH), 7.09 (d, 2H), 5.27 (d, 2H), 4.67 (s, ~ Co~CH C H 2H), 4.31 (s, 2H), 2.47 ~ 2 6 5 (t, 2H), 1.46 (quint., ~ 2H), 1.21 (sext., 2H), - " ~' 0.76 (t, 3H).
Example 182 ~ 10.81 (br ~, lH), N ~ Cl 9.02 (br s, lH), 7.55-- ~N ~ 7.35 (m, 6H), 7.11 (d, 2H), 5.28 (br 6, 3H), ~CON~O~ 4.34 (d, 2H), 2.50 (t, ~ 2H), 1.49 (quint., 2H), 1.25 (sext., 2H), 0.78 (t, 3H).
Example 183 PART A: Preparation of l-t(2'-Aminobiphenyl-4-yl) methyl]-2-butyl-4-chloro-5-hydroxymethyl-imidazole This compound was prepared according to the procedure described in Example 141, Part A. From 3.30 q of 1-[(2'-nitrobiphenyl-4-yl)methyl]-2-butyl-4-chloro-5-hydroxymethylimidazole, 1.60 q of iron powder, 3.20 ml of acetic acid, and 160 mL of methanol there was obtained 2.05 9 of 1-[(2'-aminobiphenyl-4-210 1 33409~
yl)methyl1-2-butyl-4-chloro-5-hydroxymethylimidazole.
NMR (200 MHz, CDC13) ~ 7.45 (d, 2H) 7.23-7.08 (m, 4H); 6.89-6.77 (m, 2H): 5.27 (s, 2H); 4.55 (br 6, 2H):
2.62 (t, 2H); 1.69 (quint., 2H); 1.37 (6ext., 2H);
0.88 (t, 3H).
PART B: Preparation of l-t(2'-Aminobiphenyl-4-yl)-methyl]-2-butyl-4-chloro-5-(2-methoxy-ethoxymethoxYmethyl)imidazole Thi6 compound was prepared according to the procedure described in Example 180, Part A. From 2.03 g of l-t(2~-aminobiphenyl-4-yl)methyl~-2-butyl-4-chloro-5-hydroxymethylimidazole, 3.75 mL of 1.6 M
n-butyllithium/hexane, 0.75 ml of t-butanol, 0.75 ml f 2-methoxyethoxymethyl chloride, and 25 ~L of tetrahydrofuran there was obtained 0.84 9 of 1-[(2~-aminobiphenyl-4-yl)methyl]-2-butyl-4-chloro-5-(2-methoxyethoxymethoxymethyl)imidazole. NMR (200 MHz, CDC13) ~ 7.42 (d, 2H); 7.19-7.03 (m, 4H);
6.86 (m, 2H); 5.20 (s, 2H); 4.69 (m, 2H); 4.49 (m, 2H); 3.67 (m, 2H), 3.54 (m, 2H); 3.37 (s, 3H); 2.59 (t, 2H); 1.67 (quint., 2H); 1.34 (sext., 2H); 0.87 (t, 3H).
PART C: Preparation of l-t(2'-Trifluoroacetamido-5biphenyl-4-yl)methyl]-2-butyl-4-chloro-5-(2-methoxYetboxymethoyymethyl)imidazole To a solution of 0.84 g of 1-t(2'-aminobiphenyl-4-yl)methyl]-2-butyl-4-chloro-5-(2-methoxyethoxy-methoxymethyl)imidazole, 0.23 g of 4-dimethylamino-pyridine, 1.28 mL of triethylamine, and 10 mL of tetrahydrofuran at 25 wa~ added dropwise 1.30 mL of trifluoroacetic an~ydride. The reaction mixture was stirred at 25 for 4 hours and then was poured into 211 1 3340~2 water. The resultinq 601ution was adju6ted to pH 4 using 10% hydrochloric acid and extracted with diethyl ether. The combined organic phase6 were wa6hed with water and brine, dried over anhydrou6 sodium culfate, filtered, and concentrated in vacuo. Column chromatography afforded 0.96 g of 1-t(2~-trifluoro-acetamidobiphenyl-4-yl)methyl]-2-butyl-4-chloro-5-(2-methoxyethoxymethoxymethyl)-imidazole. N~R (200 MHz, CDC13) ~ 8.22 (d, lH): 7.89 (br ~, lH): 7.44 (m, lH): 7.36-7.29 (m, 4H): 7.12 (d, 2H): 5.23 (6, 2H): 4.68 (8, 2H): 4.49 (s, 2H): 3.65 (m, 2H): 3.54 (m, 2H): 3.37 (s, 3H): 2.56 (t, 2H): 1.67 (quint., 2H): 1.34 (sext., 2H): 0.87 (t, 3H).
PART D: Preparation of l-t(2~-Trifluoroacetamido-biphenyl-4-yl)methyl]-2-butyl-4-chloro-5-hydroxYmethylimidazole Thi6 compound was prepared according to the procedure de6cribed in Example 180, Part D. From 0.96 g f 1-[(2~-trifluoroacetamidobiphenyl-4-yl)methyl-2-butyl-4-chloro-S-(2-methoxyethoxymethoxymethyl)-imidazole there was obtained 0.35 g of 1-t(2'-trifluoroacetamidobiphenyl-4-yl)methyl1-2-butyl-4-chloro-5-hydroxymethylimidazole. NMR (200 MHz, CDC13) ~ 8.24 (d, lH): 7.89 (br 6. lH): 7.46 (m, lH); 7.32 (m, 4H): 7.15 (d, 2H): 5.30 (s, 2H): 4.55 (d, 2H); 2.60 (t, 2H): 1.67 (br t, lH), 1.70 (quint., 2H); 1.36 (6ext., 2H); 0.88 (t, 3H).
-212 1 3340q 2 Example 184 PART A: Preparation of 2-(4-Methylphenoxy)-benzoic acid To a solution of 5.95 g of ~-cresol and 7.83 g of 2-chlorobenzoic in 50 mL of dimethylformamide at 25 was added, in portions, 14.50 g of anhydrou6 pota66ium carbonate. The re~ulting mixture wa6 heated to 80, and 0.10 g of copper(I) ~odide wa6 added. The reac-tion mixture then was refluxed for 16 hour6. While 6till hot the mixture was poured onto water-ice. The resultinq 6uspen6ion was filtered, and t~e filtrate vas adjusted to pH 3.0 using aqueous bydrochloric acid. The precipitate was recovered by filtration.
The crude 601id ~a~ dis~olved in an agueou6 sodium hydroxide 601ution. This 601ution was acidified to pH 6.0 u6ing hydrochloric acid, filtered, and then acidified to pH 3Ø Filtration provided 5.67 g of 2-(4-methylphenoxyl)benzoic acid which was employed in the following reaction without further purification.
NMR (200 MHz, CDCl ): ~ 8.15 (d of d, lH); 7.42 (d of d of d, lH); 7.23-7.12 (m, 3H); 6.97 (d, 2H);
6.80 (d, lH): 2.37 (6, 3H).
~ART B: Preparation of Methyl 2-(4-methylphenoxy)-benzoate A 601ution of 37.70 g of 2-(4-methylphenoxy)-benzoic acid was 12.0 mL of concentrated sulfuric acid in 500 mL of methanol was refluxed for 14 hours. After cooling, the reaction mixture wa6 concentrated in vacuo and the residue was added to a mixture of methylene chloride and water. The organic phase wa6 6eparated, washed with saturated 60dium bicarbonate solution and brine, dried over anhydrous sodium ~ulfate, filtered, and concentrated. The crude product was kugelrohr distilled (120-135/0.025 torr) to furnish 35.08 9 of l 3340q2 methyl 2-(4-methylphenoxyl)benzoate, m.p. 31-34. NMR
(200 MHz, CDC13) ~ 7.87 (d of d, lH); 7.39 (t of d, lH): 7.11 (m, 3H); 6.88 (m, 3H); 3.81 (6, 3H): 2.30 (6, 3H).
PART C: Preparation of Methyl 2-(4-bromomethyl-Phenoxy)benzoate A 601ution of 35.08 g of methyl 2-(4-methyl-phenoxy)benzoate, 25.7 g of N-bromo6uccinimide, 0.57 q of azobi6i60butyronitrile, and 1200 mL of carbon tetrachloride wa6 refluxed for 3 hour6. After cooling to room temperature the re6ulting 6u6pen6ion wa6 filtered and then concentrated in vacuo to provide 4.51 g of crude methyl 2-~4-bromomethylphenoxy)benz-oate which wa6 u6ed in a ~ub6eguent reaction without further purification; NMR (200 MHz, CDC13): ~
7.92 (d of d, lH): 7.45 (t of d, lH): 7.16 (m, 3H):
6.90 (m, 3H); 4.49 (6, 2H): 3.83 (6, 3H).
PART D: Preparation of 2-Butyl-4-chloro-1-t4-(2-carbomethoxyphenoxy)benzyl]-5-hydroxy-methYlimidazole To a 6u6pen6ion of 7.51 g of 60dium methoxide in100 mL of dimethylformamide at 25 wa6 added a solution of 26.50 g of 2-butyl-4(5)-chloro-5(4)-hydroxymethyl-imidazole in 100 mL of DHF. The re6ulting mixture wa6 6tirred at 25 for 0.25 hour6: to thi6 mixture wa6 added dropwi6e a 601ution of 45.1 g of methyl 2-(4-bromomethylphenoxy)benzoate in 100 mL of DMP.
~ inally, the reaction mixture wa6 6tirred at 40 for 4 hour6. After cooling to 25, the 601vent wa6 removed in vacuo. The re6idue wa6 di6601ved in ethyl acetate, and thi6 601ution wa6 wa6hed with water and brine, dried over anhydrou6 60dium 6ulfate, filtered, and concentrated. Column chromatography on 6ilica gel 1 3340~2 (elution:10-25~ ethyl acetate/benzene) afforded 7.80 g of 2-butyl-4-chloro-1-t4-(2-carbomethoxyphenoxy)-benzyl]-5-hydroxymethylimidazole. NMR (200 MHz, CDC13) ~ 7.92 (d, lH): 7.48 (t, lH): 7.21 (t, lH):
6.93 (m, 5H): 5.21 (6, 2H): 4.48 (6, 2H): 3.79 (6, 3H); 2.56 (t, 2H); 1.65 (~uint., 2H): 1.34 (6ext., 2H): 0.88 (t, 3H).
PART E: Preparation of 2-Butyl-4-chloro-1-t4-(2-carboxyphenoxy)benzyl~-5-hydroxymethyl-imidazole A solution of 7.70 q of 1-t4-(2-carbomethoxy-phenoxy)benzyl]-2-butyl-4-chloro-5-hydroxymethyl imidazole in 250 mL of ethanol and 125 ~L of 10~
aqueou6 60dium hydroxide was refluxed for 5 hour6.
After cooling, the reaction mixture wa6 filtered, and the 601vent was removed in vacuo. The re6idue wa6 di6solved in water, and the 601ution wa6 acidified to pH 3.5 u6ing hydrochloric acid. The precipitated 601id wa~ recovered by filtration and recry6tallized from acetone to furni6h 6.52 g of 2-butyl-4-chloro-1-[4-(2-carboxyphenoxy)benzyl~-5-hydroxymethylimidazole, m.p. 178-180. NMR (200 MHz, DMS0) ~ 7.79 (d, lH):
7.53 (t, lH): 7.23 (t, lH): 7.07 (d, 2H): 6.94 (d, lH): 6.87 (d, 2H): 5.18 (6, 2H): 4.32 (6, 2H); 2.47 (t, 2H): 1.46 (quint., 2H): 1.23 (6ext., 2H): 0.78 (t, 3H).
The following compound6 have been or could be prepared by the above procedure6.
Table 12 R 61 N~ R 8 No. R R R ~ _ MP(C) 185 n-butyl Cl CH20H4-S ~ 166-167 C~o2H
186 n-butyl Cl CH20H 4-N
Co2H
187 n-butyl Cl CH20H 4-N
188 n-propyl H CH20H 4-S
Co2H
189 n-propyl Cl CH20H 4-S
190 CH20CH2CH2CH2 Cl CH20H 4-S
C~
191 n-butyl Cl CH20H q-N
,CH2 -Example 192 PART A: Preparation of 1-(4-BenzyloxybenZyl)-2-bUtyl-4-chloro-S-hYdroxymethylimidazole To a 6u6pension of 1.43 g of sodium methoxide in 20 mL of dimethylformamide at 25 was added a solution of 5.00 g of 2-butyl-4(5)-chloro-5(4)-hydroxymethyl-imidazole in 15 mL of dimethylformamide lDMF). The re6ulting mixture wa6 stirred at 25 for 0.25 hour6, and then to this mixture wa6 added dropwi6e a 601ution f 4-benzyloxybenzyl chloride in 15 ~L of DMP.
Finally, the reaction mixture wa6 6tirred at 40, the 601vent wa6 removed in vacuo. The re6idue wa6 dissolved in ethyl acetate, and this solution was wa6hed wit~ water and brine, dried over anhydrou6 60dium sulfate, filtered, and concentrated. Column chromatography on silica gel (elution: 10-25~ ethyl acetate/benzene) afforded 3.27 g of 1-(4-benzyloxy-benzyl)-2-butyl-4-chloro-5-hydroxymethylimidazole:
m.p. 115-116: NMR (200 MHz, CDC13): ~ 7.39 (m, 5H); 6.94 (6, 4H): 5.15 (s, 2H): 5.04 (6, 2H): 4.47 (bs, 2H): 2.56 (t, 2H): 2.07 (bs, lH): 1.63 (quint., 2H): 1.32 (sext., 2H): 0.87 (t, 3H).
PART B: Preparation of 1-(4-Hydroxybenzyl)-2-butyl-4-chloro-5-hYdroxymethylimidazole A mixture of 0.50 g of 1-(4-benzyloxybenzyl)-2-butyl-4-chloro-5-hydroxy~ethylimidazole, 0.50 g of 10%
palladium/carbon and 40 mL of tetrahydrofuran was 6tirred at room temperature under hydrogen gas (1 atm.) for 6 hours. The mixture ~as filtered through Celite~ under nitrogen, and the re6ulting solution was concentrated in vacuo; The crude product was extracted with hot chloroform. After cooling, the chloroform mixture was concentrated in vacuo, and the resulting 601id was washed with hexane to afford 0.16 g of l-(4-hydroxybenzyl)-2-butyl-9-chloro-5-hydroxy-methylimidazole: NMR (200 MHz, DMS0-d6): ~ 9.43 (6, lH): 6.81 (A2B2, 4H): 5.21 (t, lH): 5.10 (6, 2H): 4.33 (d, 2H): 2.47 (t, 2H); 1.44 (quint 2H): 1.23 (6ext., 2H); 0.79 (t, 3H).
PART C: Preparation of l-t4-(2-Cyanobenzyloxy)benzyl]-2-butYl-4-chloro-5-~ydroyy~nethylimidazole To a 601ution of 1.00 g of 1-(4-hydroxybenzyl)-2-butyl-4-chloro-5-~ydroxymethylimidazole in 15 mL of DM~ at 25 wa6 added 0.185 g of ~odium methylate, and the re6ulting mixture wa6 6tirred at 25 for 0.25 hours. To thi6 mixture was then added a ~olution of 0.80 g of a-bromo-o-tolunitrile in 5 ~L of DM~. The reaction mixture wa6 6tirred at 25 for 16 hour6. The 601vent wa6 removed in vacuo, and the residue di6-601ved in ethyl acetate. Thi6 solution wa6 wa6hed with water and brine, dried over anhydrou6 60dium 6ulfate, filtered, and concentrated in vacuo. Column chromatography on silica gel (elution: 10-25% ethyl acetate/benzene) provided 0.76 g of 1-t4-(2-cyano-benzyloxy)benzyl]-2-butyl-4-chloro-5-hydroxymethyl-imidazole: NMR (200 HHz, CDC13): ~ 7.73-7.59 (m, 3H); 7.44 (m, lH): 6.96 (6, 4H); 5.23 (6, 2H): 5.14 (6, 2H): 4.50 (d, 2H): 2.57 (t, 2H): 1.66 (quint., 2H); 1.33 (6ext., 2H): 0.87 (t, 3H).
PART D: 1-t4-(2-Cyanobenzyloxy)benzyl~-2-butyl-4-chloro-5-cYanomethylimidazole To a 601ution of 0.?6 g of 1-t4-(2-cyanobenzyl-oxy)benzyl]-2-butyl-4-chloro-5-hydroxymethylimidazole in 20 mL of chloroform at 25 wa6 added dropwi6e 0.95 mL of thionyl chloride and the mixture wa6 6tirred at 25 for 2 hour6. The solvent wa6 removed in vacuo.
-218 ~ 334092 The residue wa6 di6solved in 20 mL of toluene, and then the toluene wa6 removed in vacuo. Finally, the residue was di6601ved in 10 mL of dimethyl 6ulfoxide, and the re6ulting 601ution wa6 added to a 601ution of 0.71 g of sodium cyanide in lO mL of dimethylsulfoxide.
The mixture wa6 6tirred at 25 for 1 hour and then poured into water. Thi6 emulsion wa~ extracted with ethyl acetate: and the combined organic pha6es were washed with water and brine, dried over anhydrou6 60dium 6ulfate, filtered, and concentrated. Column chromatography on 6ilica gel telution 0-25~ ethyl acetate/benzene) afforded 0.67 g of 1-t4-(2-cyano-benzyloxy)benzyl]-2-butyl-4-chloro-5-cyanomethyl-imidazole: NMR (200 MHz, CDC13): ~ 7.79-7.60 (m, 3H): 7.47 (m, lH): 7.00 (8, 4H): 5.24 (6, 2H): 5.14 (6, 2H); 3.46 (6, 2H): 2.66 (t, 2H): 1.71 (quint., 2H): 1.40 (6ext., 2H): 0.92 (t, 3H).
PART ~: l-t4-(2-Carboxybenzyloxy)benzyl]-2-butyl-4-chloroimidazole-5-acetic acid A 601ution of 0.65 g of 1-t4-(2-cyanobenzyloxy)-benzyl]-2-butyl-4-chloro-5-cyanomethylimidazole in 20 mL of ethylene glycol and 10 mL of 10% aqueous 60dium hydroxide wa6 refluxed for 14 hour~. After cooling, the reaction mixture was filtered, and the solvent wa6 removed in vacuo. The re~idue wa6 di6solved in water, and the 601ution wa6 acidified to pH 3.5 u6ing hydro-chloric acid. The precipitated 601id wa6 recovered by filtration and recry6tallized from aqueous ethanol to furnish 0.21 g of 1-14-(2-carboxybenzyloxy)benzyl~-2-butyl-4-chloroimidazole-5-acetic acid, m.p.
170-172: NMR (200 MHz, DMSO-d6): ~ 12.9 (b8, 2H):
7.94 (d, lH): 7.61 (d, lH): 7.60 (t, lH): 7.46 (t, lH): 6.99 (6, 4H): 5.45 (s, 2H); 5.11 (6, 2H): 3.49 (6, 2H): 2.52 (t, 2H); 1.48 (quint., 2H): 1.24 (6ext., 2H); 0.82 (t, 3H).
Example 193 PART A: Preparation of 1-(4-Hydroxybenzyl)-2-butyl-5-hYdroxymet~ylimidazole A mixture of 1.00 g of 10% palladium/carbon and 1.00 g of 1-(4-benzyloxybenzyl)-2-butyl-4-chloro-5-hydroxymethyl imidazole in 20 mL of methanol wa6 stirred at 25 for fi~e minutes. ~y~rogen ga6 wa6 bubbled into the 601ution, and t~e mixture was 6tirred under hydrogen ga6 (1 atm.) at 25 for 2 ~our6. The mixture wa6 filtered, and the resulting 601ution concentrated in vacuo to furni6h 0.75 g of 1-(4-hydroxybenzyl)-2-butyl-5-hydroxymethylimidazole: NMR
(200 MHz, DMSO-d6): ~ 9.75 (b6, lH); 7.55 (6, lH):
6.91 (A2B2, 4H): 5.80 (b6, lH): 5.35 (6, 2H): 4.45 (6, 2H): 2.89 (t, 2H): 1.44 (quint, 2H): 1.21 (6ext., 2H): 0.80 (t, 3H).
PART B: Preparation of l-t4-(2-CarboxybenzyloYy)-benzYl~-2-butYl-s-hydroxymethylimidazole The title compound wa6 prepared from 1-(4-hydroxybenzyl)-2-butyl-5-hydroxymethylimidazole u6ing the alkylation and hydroly6i6 procedures described in Example 192, Part~ C and E, m.p. 115-116 NMR (200 MHz, DMSO-d6): ~ 7.92 (d, lH): 7.59 (m, 2H): 7.43 (m, lH): 6.95 (A2B2, 4H): 6.74 (6, lH): 5.40 (6, 2H): 5.11 (~, 2H): 4.31 (6, 2H): 2.48 (t, 2H): 1.47 (quint., 2H): 1.23 (6ext., 2H): 0.77 (t, ~H).
ExamPle 194 PART A: Preparation of l-t4-(2-Cyanobenzyloxy)benzyl]-2-butYl-4-chloro-5-methoxymethylimidazole To a 601ution of 0.29 g of 1-t4-(2-cyanobenzyl-oxy)benzyl]-2-butyl-4-chloro-5-hydroxymet~ylimidazole in 8.0 mL of dimethyl 6ulfoxide at 25 wa6 added 0.93 g of potas~ium t-butoxide followed by 0.060 mL of 1 3340q2 methyl iodide. The reaction mixture was stirred at 25 for 2.5 hours and then was poured into water. The aqueous emulsion was extracted with ethyl acetate; the organic phases were combined and washed with water and brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. Column chromatography on silica gel (elution: 5-25~ ethyl acetate~benzene) furnished 0.17 g of 1-t4-(2-cyanobenzyloxy)benzyl]-2-butyl-4-chloro-5-methoxymethylimidazole: NMR (200 MHz, CDC13): ~ 7.72-7.57 (m, 3H); 7.43 (m, lH); 6.94 (s, 4H); 5.22 (s, 2H); 5.04 (s, 2H); 4.27 (s, 2H); 3.26 (8, 3H); 2.56 (t, 2H); 1.65 (quint., 2H); 1.33 (sext., 2H); 0.88 (t, 3H).
5 PART B: Preparation of 1-~4-(2-Carboxybenzyloxy)-benzyl]-2-butyl-4-chloro-5-methoxymethyl-imidazole The title compound was prepared from 1-[4-(2-cyanobenzyloxy)benzyl]-2-butyl-4-chloro-5-methoxy-methylimidazole via the hydrolysis procedure describedin Example 192, Part E; NMR (200 MHz, DMSO-d6):
7.91 (d, lH); 7.57 (m, 2H); 7.42 (m, lH); 6.97 (A2B2, 4H); 5.41 (s, 2H): 5.09 (s, 2H); 4.27 (3, 2H); 3.17 (s, 3H); 2.49 (t, 2H); 1.44 (quint, 2H);
1.21 (sext., 2H); 0.79 (t, 3H).
The compounds shown in Table 13 where X =
-OCH2- were prepared or could be prepared employing the above procedures of Examples 192-194 and procedures previously described.
221 1 3~4092 Table 13 N--~
'R6~N ~iR8 Ex 6 R7 R8 ~R13 MP ( C ) 195 n-butyl Cl CH20H 4-ocH2~3 (oil )a 196 n-butyl Cl CH20H 3-ocH2~3 19 7 n - bu t y 1 C 1 CH2 OCH2 CH 3 4 - OCH
198 n-butyl Cl CH20CH2C6HC 4-OCH
C~H
199 n-butyl Cl CH20CCH3 4-OCH2~ ~oil)b 3 2 2 2 g - OCH
201 n-propyl CF3 CH20H 4~ H
1 3340q2 a NMR (200 MHz, DMS0-d6): ~ 7.91 (d, lH):
7.58 (m, 2H); 7.42 (m, lH) 6.98 (A2B2, 4H): 5.42 (s, 2H); 5.15 (s, 2H): 4.32 (s, 2H): 2.48 (t, 2H): 1.44 (quint., 2H): 1.23 (6ext., 2H): 0.79 (t, 3H).
b NMR (200 MHz, CDC13): ~ 8.13 (d, lH):
7.75 (d, lH): 7.58 (t, lH) 7.39 (t, lH) 6-88 (A2B2, 4H): 5.51 (s, 2H): 5.04 (s, 2H): 4.95 (s, 2H): 2.60 (t, 2H): 1.83 (fi, 3H): 1.65 (quint., 2H): 1.32 (sext., 2H) 0.85 (t, 3H).
ExamPle 202 PART A: MethYl 2-[4-(BromomethYl)benzoyllbenzoate Methyl 2-toluylbenzoate (CA reg. # 6424-25-5:
available by simple e6terification of commercially available 2-toluylbenzoic acid) (10.00 g, 39.3 mmol, 1 eq), N-bromosuccinimide (7.00 g, 39.3 mmol, 1 eq), benzoyl peroxide (1.0 g) and 100 mL carbon tetra-chloride were mixed and refluxed overnight (peroxide added last). The mixture was filtered and 250 mL of a 100 g/l aqueous solution of ~odium bisulfite solution was added. The layers were separated and the organic layer was dried (MgS04) and concentrated. The brown solid residue was recrystallized from ether/hexane to give 6.47 g of product; m.p. 88.2-91.5. NMR (200 MHz, CDC13) ~ 8.07 (d, lH, J= 7Hz): 7.82-7.07 (m, 7H): 4.50 (s, 2H): 3.67 (s, 3H). Anal. Calcd. for C16H13O3Br:
C, 57.68: H, 3.93: Br, 23.98. Pound: C, 57.84: H, 4.04: Br 23.99. Mass Calcd. for C16H13O3Br:
332.0048. Found: 332.0033.
1 3}409~
PART B: Preparation of 2-Butyl-1-~4-(2-carbomethoxy-benzoyl)benzyl]-4-chloro-5-hydroxymethyl-imidazole To a 601ution of 2-butyl-4-chloro-5-(hydroxy-methyl)imidazole (11.12 g, 54 mmol, 1 eq) in 200 mL
methanol was added dropwi~e a fre6hly prepared 60dium methoxide 601ution (1.36 g Na, 59 mmol, 1.1 eg in 50 mL MeOH). After 6tirring for O.S ~our6, the methanol was removed in vacuo and the re6ultant gla66 wa6 dis601ved in 200 mL DMF. To thi6 mixture wa6 added a 601ution of methyl 2-t4-(bromomethyl)benzoyl]benzoate (18.00 g, 59 mmol, 1.1 eg) in DM~ and the entire content6 wa~ 6tirred overnight under N2 at room temperature. The 601vent wa6 then removed in ~acuo and the re~idue dis601ved in 500 mL ethyl acetate and 500 mL H20. The layer6 were 6eparated and the aqueous layer wa~ extracted twice with 500 mL portion6 of ethyl acetate. The organic layer~ were dried and concentrated and the crude product fla6h chroma-tographed to ~eparate the two regioi60mer~ in 60:40hexane/ethyl acetate over 6ilica gel. The fa6ter moving i60mer was i601ated to yield 14.72 g of a gla~y 601id. NMR (200 MHz, CDC13) ~ 8.03 (d, lH, J=
7Hz): 7.67 (m, 4H): 7.36 (d, lH, J= 7Hz): 7.05 (d, 2H, J= 7Hz); 5.28 (6, 2H): 4.43 (6. 2H): 3.63 (6, 3H):
2.53 (t, 2H, J= 7Hz): 1.60 (t of t, 2H, J= 7,7Hz):
1.30 (t of q, 2H, J= 7,7Hz): 0.87 (t, 3H, J= 7Hz).
' 25 26 3 4 5 Found: 586.1285.
1 3~4092 PART C: 2-Butyl-l-t4-(2-Carboxybenzoyl)benzyl~-4-chloro-5-(hYdroxymethyl)imidazole 2-Butyl-l-t4-(2-carbomethoxybenzoyl)benzyl~-4-chloro-5-hydroxymethylimidazole (500 mg, 1.13 mmol, 1 eq), 0.5 N KOH in methanol (2.27 mL, 1.14 mmol, 1 eq), and O.S mL of H2O were mixed and stirred.
After 6 hours, water (50 mL) was added and the pH was lowered to 3-5 with conc. HCl. The agueous mixture wa6 extracted with ethyl acetate (3 x SO mL) and the organic layers were dried (HgSO4) and concentrated to gi~e 200 mg of product: m.p. 90.0-95Ø NMR (200 MHz, CDC13) ~ 8.05 (d, lH, J. 7Hz); 7.48-7.75 (m, 4H); 7.37 (d, lH, J= 7Hz); 7.00 (d, 2H, J= 7Hz); 5.20 (6, 2H); 4.40 (6, 2H); 2.45 (t, 2H, J~ 7Hz); 1.50 (t f t, 2H, J= 7Hz); 1.25 (t of g, 2H, J= 7Hz): 0.79 (t, 3H, J= 7Hz). Anal. Calcd. for C23H23ClN2O4-(CH30H): C, 62.81: H, 5.93: ~ound: C, 62.95: H, S.99. Mass spec-trum shows M-H2O. Mass Calcd. for C23H23ClN2O4-H2O:
408,1235. Found: 408.1228.
ExamPle 203 Preparation of 2-n-Butyl-1-~4-(2-carboxybenzoyl)-benzyl-4-hydroxymethyl-5-chlorimidazole Using the procedure of Example 202, 2-n-butyl-1-t4-(2-carboxybenzoyl)benzyl]-4-hydroxymethyl-S-chloro-imidazole was prepared from 2-n-butyl-1-t4-(2-carbo-methoxybenzoyl)benzyl]-4-hydroxymethyl-S-chloro-imidazole, m.p. 214.0-216Ø NMR (200 MHz, CDC1 DMSO-d6) ~ 8.07 (d, lH, J. 7,7Hz): 7.32 (d, lH, J=
7Hz): 7.10 (d, 2H, J= 7Hz): S.l9 (s, 2H) 4.50 (s, 2H): 2.61 (t, 2H, J= 7Hz): 1.63 (t of t, 2H, J~
7,7Hz); 1.33 (t of q, 2H, J= 7,7Hz): 0.87 (t, 3H, J=
7Hz). Titration of the product with 1.000 N NaOH
showed the presence of exactly one acidic functionality. Anal. Calcd. for C23H23ClN2O4:
1 3340~2 C, 64.71; H, 5.43; N, 6.56. Pound: C, 64.75; H, 5.30; N, 6.65.
Example 205 PART A: Preparation of 2-Butyl-l-t4-(2-carbomethoxy-benzoyl)benzyl]-4-chloro-5-(chloromethyl)-imidazole, hYdrochloride 6alt 2-Butyl-1-~4-(2-carbomethoxybenzoyl)benzyl~-4-chloro-5-hydroxymethylimidazole (5.00 g, 11.3 ~ol, 1 1 eq) wa~ di6~01ved in 50 mL chloroform and to t~i6 solution wa6 dropwi6e added thionyl chloride (4.13 mL, 56.6 mmol, S eq) with 6tirring at room temperature.
After 4 hour6, the 601vent and exce66 thionyl chloride were removed by rotary evaporation. Toluene (100 mL) wa6 added to the recidue and the ~olvent again removed by rotary evaporation. Toluene wa6 again added and while evaporating the second time, product cry6tallized from 601ution yielding 2.91 g of a white ~olid: m.p.
139.0-143.5. NMR (200 MHz, CDC13) ~ 8.07 (d, lH, J= 7Hz): 7.~0 (d, 2H, J= lOHz): 7.68 (t, lH, J= 7Hz):
7.58 (t, lH, J= 7Hz): 7.35 (d, lH, J= 7Hz); 7.13 (d, 2H, J= lOHz): 5.43 (~, 2H): 4.42 (6, 2H): 3.67 (6, 3H): 2.96 (m, 2H): 1.75 (m, 2H): 1.39 (m, 2H): 0.88 (t, 2H, J= 7Hz). Mas6 Calcd. for C24H24C12N203:
458.1162. ~ound: 458.1160.
PART B: 2-Butyl-1-[4-(2-Carbomethoxybenzoyl)-benzy~]-4-chloro-5-((1,2,4-triazol-1-yl)-methYl~imidazole 2-Butyl-l-t4-(2-carbomethoxybenzoyl)benzyl]-4-chloro-5-chloromethylimidazole-HCl ~alt (1.00 g, 2.06 mmol, 1.0 eq), pota66ium triazolide (0.26 g, 2.39 mmol, 1.1 eq) and DM~ (50 mL) were mixed and heated at 90 under N2 overnight. The reaction was wor~ed up by removing the solvent in vacuo, taking up the residue in water (200 mL) and ethyl acetate (200 mL), 6epa-rating the layers and extracting the aqueou6 with ethyl acetate (2 x 200 mL). The organic layer~ were dried (MgSO4) and concentrated; the re~idue wa6 fla~h chromatographed over silica gel in 100% ethyl acetate to give 780 mq of a white gla6~y ~olid. NMR
(200 MHz, CDC13) ~ 8.05 (~, lH): 8.05 (d, lH, J= 7Hz):
7.83 (~, lH); 7.74 (d, 2H, J= lOHz); 7.66 (t, lH, J=
7Hz); 7.58 (t. lH, J= 7Hz); 7.33 (d, lH, J= 7Hz); 6.98 (d, 2H, J= 7Hz); 5.37 (6, 2H); 5.15 t~, 2H); 3.69 (~, 3H); 2.56 (t, 2H, J= 7Hz); 1.73 (m, 2H); 1.36 ( t of q, 2H, J= 7,7Hz); 0.87 (t, 3H, J 7Hz). Ma~ Calcd.
for C26H26ClN5O3: 491.1722. ~ound: 491.1816.
The following intermediate~ were prepared by the above procedure u~ing the appropriate nucleophile, imidazole ~tarting material, and ~olvent.
-N ~
R6~N ~R8 S ~
l O
~ `CR
R6 R R _ ~P(C) n-butyl Cl CH2-N ~ N ~ (oil) ~ 2 3 D-butyl Cl CH2N3 ~ 127.0-129.5 n-butyl Cl CH2CN ~ (oil) n-butyl Cl CH20CH3 ~ (601id) a NMR (200 MHz, CDC13) ~ 8.05 (d, lH, J=
7Hz): 7.72 (d, 2H, J= 8Hz); 7.65 (t, lH, J=
7Hz); 7.56 (t, lH, J= 7Hz); 7.36 (d, lH, J~
7Hz): 7.33 (b6, lH): 7.00 (b6, lH): 6.89 (d, 25 2H, J= 8Hz); 6.78 (bs, lH); 4.91 (6, 2H);
4.88 (6, 2H); 3.67 (~, 3H); 2.54 (t, 2H, J=
7Hz); 1.65 (t of t, 2H, J= 7,7Hz); 1.33 (t of q, 2H, J= 7,7Hz); 0.85 (t, 3H, J= 7Hz).
b NMR (200 MHz, CDC13) ~ 8.05 (d, lH, J=
30 7Hz); 7.76 (d, 2H, J= lOHz); 7.64 (t, lH, J=
7Hz); 7.56 (t, lH, J= 7Hz); 7.36 (d, lH, J=
7Hz): 7.06 (d, 2H, J= lOHz); 5.24 (~, 2H);
3.66 (~, 3H); 3.47 (6, 2H); 2.63 (t, 2H, J=
7Hz); 1.70 (t of t, 2H, J= 7,7Hz); 1.37 (t of 35 q, 2H, J= 7,7Hz); 0.89 (t, 3H, J= 7Hz).
- 1 334~2 c NMR (200 MHz, CDC13) ~ 8.05 (d, lH, J=
8Hz); 7.72 (d, 2H, J= 8Hz); 7.61 (m, 2H);
7.38 (d, lH, J= 7Hz); 7.04 (d, 2H, J= 7Hz);
5.20 (6, 2H); 4.26 (6, 2H); 3.63 (6, 3H);
3.21 (6, 3H); 2.50 (t, 2H, J= 7Hz); 1.65 (m, 2H); 1.29 (m, 2H): 0.84 (t, 3H, J= 7Hz).
PART C: 2-Butyl-l-t4-(2-Carboxybenzoyl)benzyl]-4-c~loro-5-((1~2~4-triazol-l-Yl)methyl)imidazole 102-Butyl-l-t4-(2-carbomethoxybenzoyl)benzyl]-4-c~loro-5-((1,2,4-triazol-1-yl)met~yl)imidazole (780 mg, 1.59 mmol, 1 eq), 0.5 N ~OH in MeOH (6.34 mL, 3.17 mmol, 2 eq) and methanol (20 mL) were mixed and 6tirred at 20 under N2. After 2.5 ~our6, one more equivalent of O.S N KOH in ~eOH wa6 added. After 6even hour6, the 601ution wa6 acidified to a pH of 4 with 1 N HCl, and 200 mL each of et~yl acetate and water wa6 added. The layer6 were 6eparated and the aqueou6 layer wa6 extracted with ethyl acetate (2 x 200 mL). T~e organic layer6 were dried (MgSO4) and concentrated to give 640 mg of a white gla66y 6clid:
m.p. 180.0-188Ø NMR (200 MHz, CDC13) ~ 7.94 (d, lH, J= 7Hz); 7.74 (6, lH): 7.65 (6, lH); 7.55 (d, 2H, J= 7Hz): 7.70-7.50 (m, 3H); 6.67 (d, 2H, J= 7Hz); 5.34 (6, 2H): 5.14 (6, 2H); 2.64 (t, 2H, J= 7Hz); 1.74 (t of t, 2H, J= 7,7Hz): 1.36 (t of q, 2H, J= 7,7Hz); 0.89 (t, 3H, J= 7Hz). Anal. Calcd. for C25H24ClN5O3-EtOAc:
C, 61.53; H, 5.70; N, 12.37. Found: C, 61.72; H, 5.19, N, 12.27.
Example6 205-207 in Table 14 were prepared by t~e procedure de6cribed in Example 203, Part C u6ing t~e appropriate imidazole 6tarting material6.
Table 14 1 334092 N ~
R6 ~ N ~ R8 ~3~o ~
No. R6 R R R13 MP(C) 205 n-butyl Cl CH2-N ~ CO2H (oil)a 206 n-butyl Cl CH2~3 C02H 188.0-190.0 207 n-butyl Cl CH20CH3 C02H 210.0-211.5 a NMR (200 ~Hz, CDC13/D20 exchange) ~
9.67 (~, lH); 7.98 (d, lH, J= 7Hz); 7.63 (t, lH, J= 7Hz); 7.55 (t, 2H, J= 7Hz); 7.41 (d, 2H, J= lOHz); 7.41 (d, lH, J= 7Hz); 7.09 (8, lH); 7.08 (6, lH); 6.70 (d, 2H, J= lOHz);
5.65 (~, 2H); 5.58 (~, 2H); 2.59 (t, 2H, J= 7Hz); 1.71 (t of t, 2H, J= 7,7Hz); 1.36 (t of q, 2H, J= 7,7Hz); 0.87 (t, 3H, J= 7Hz).
ExamPle 208 PART A: Preparation of 2-Butyl-l-t4-(2-carbomethoxy-benzoyl)benzyl]-4-chloro-5-[(lH-tetrazol-5-Yl)metbyl~imidazole The title compound was prepared from 2-butyl-1-[4-(2-carbomethoxybenzoyl)benzyl~-4-chloro-5-(cyano-methyl)imidazole by the procedure described in Example 26; NMR (200 MHz, DMS0-d6) ~ 8.00 (d, lH, J= 7Hz); 7.78 (t, lH, J= 7Hz): 7.70 (t, lH, J = 7Hz): 7.50 (d, 2H, J= 8Hz): 7.46 (d, lH, J= 7Hz): 7.05 (d, 2H, J= 8Hz):
5.35 (6, 2H): 4.20 (6, 2H): 3.57 (8, 3H): 2.52 (t, 2H, J= 7Hz): 1.52 (t of t, 2H, J= 7,7Hz): 1.27 (t of q, 2H, J= 7,7Hz): 0.70 (t, 3H, J= 7Hz). Anal. Calcd. for C25H25ClN6O3: C, 60.91: H, 5.11: N, 17.05- Pound:
C, 60.84: H, 5.12: N, 16.71. Ha66 Calcd. for C25H25ClN6O3: 492.1686. Eound: 492.1614.
PART B: Preparation of 2-Butyl-l-t4-(2-carboxy-benzoyl)benzyl]-4-chloro-5-t(lH-tetrazol-5-Yl)methyl~imidazole The title compound wa6 prepared from 2-butyl-1-t4-(2-carbomethoxybenzoyl)benzyl]-4-chloro-5-t(lH-tetrazol-5-yl)methyl]imidazole by the procedure de6cribed in Example 202, Part C: m.p. 228.0-229.5.
NMR (200 MHz, DMS0-d6) ~ 7.98 (d, lH, J= 7Hz): 7.73 (t, lH, J= 7Hz): 7.69 (t, lH, J= 7Hz): 7.55 (d, 2H, J= 8Hz): 7.38 (d, lH, J= 7Hz): 7.05 (d, 2H, J= 8Hz):
5.32 (6, 2H): 4.16 (6, 2H): 2.50 (t, 2H, J= 7Hz): 1.50 (t of t, 2H, J= 7,7Hz): 1.24 (t of q, 2H, J= 7,7Hz):
0.80 (t, 3H, J= 7Hz). Anal. Calcd. for C24H23ClN603:
C, 60.19: H, 4.84: N, 17.55. ~ound: C, 59.73: H, 4.61:
N, 17.82.
ExamPle 209 PART A: Preparation of 5-Aminomethyl-2-n-butyl-l-t4-(2-carbomethoxybenzoyl)benzyl]-4-chloroimidazole, chromium 6alt 5-Azidomethyl-2-n-butyl-1-~4-(2-carbomethoxy-benzoyl)benzyl]-4-chloroimidazole (4.24 g, 9.1 mmol, 1 eq), chromium (II) chloride (6.75 g, 54.7 mmol, 6 eq), acetone (40 mL) and water (13 mL) were mixed 231 I 3340~2 and 6tirred tthe chromium (II) chloride being added last). After Nz evolution had 6topped, the reaction mixture was diluted with 6aturated aqueou6 sodium bicarbonate (250 mL) and extracted with ethyl acetate (3 x 250 mL). The organic layers were dried (NgS04) and concentrated to give 601id6 which after wa6hing with et~er gave 2.92 g of white 601id (chromium 6alt of the product): m.p. 178.5-181Ø NMR (200 MHz, CDC13/DMSO-d6) ~ 8.85 (b6, lH); 8.05 (d, lH, J~ 7Hz):
7.57-7.25 (m, 4H); 7.36 (d, lH, J= 7Hz); 7.06 (bd, 2H, J= 7Hz); 5.67 (b6, 2H); 3.85 (b6, 2H); 3.67 (6, 3H);
2.60 (t, 2H, J= 7Hz); 1.~8 (m, 2H); 1.37 (t of q, 2H, J= 7,7Hz); 0.89 (t, 3H, J~ 7Hz). Mas6 Calcd. for C24H26ClN303: 439.1663. Found: 439.1663. Anal.
Calcd- for Cr(C24H26ClN33)2 N, 9.02. Found: C, 61.46; H, 5.59; N, 8.54.
PART B: Preparation of 2-Butyl-4-chloro~ 4-(2-carbomethoxybenzoyl)benzyl]-5-(methoxy-carbonYlaminomethyl)imidazole 5-Aminomethyl-2-butyl-1-[4-(2-carbomethoxy-benzoyl)benzyl]-4-chloroimidazole (chromium 6alt) (500 mg, 1.14 mmol, 1 eq) wa6 di6solved in a mixture of 1.00 N NaOH (1.14 mL, 1.14 mmol, 1 eq) and H20 (10 mL). Tetrahydrofuran may be added to a6si6t solvation. The 601ution was cooled to 0 when methyl chloroformate (0.176 mL, 2.28 mmol, 2 eq) in THF (5 mL) wa6 610wly dripped in, in five equal portion6, alternating with five portion6 of 1.00 N NaOH (total of 1.14 mL, 1.14 mmol, 1 eg). ~hen the addition wa6 complete, the mixture wa6 6tirred at room temperature for 4 hours. Water (100 mL) was added and the pH
adjusted to 5 with lN HCl. The aqueou6 wa6 extracted with ethyl acetate (3 x 100 mL), the organic layers -dried (MgS04) and stripped to give a white glass (560 mg). Flash chromatography in 100% ethyl acetate to 100% isopropanol yielded 280 mg of product as an oil. NMR (200 MHz, CDC13) ~ 8.10 (d, lH, J= 7Hz):
7.75 (d, 2H, J= 7Hz); 7.75-7.56 (m, 2H); 7.39 (d, lH, J= 7Hz): 7.02 (d, 2H, J= 7Hz~; 5.32 (6, 2H): 4.83 (m, lH): 4.28 (d, 2H, J= 7Hz): 3.70 (s, 3H); 3.57 (6, 3H);
2.58 (t. 2~, J= 7Hz); 1.72 (t of t, 2H, J= 7,7Hz);
1.37 (t of q, 2H, J= 7,7Hz); 0.92 (t, 3H, J= 7Hz).
Mass Calcd. for C26H28clN305 497.1717.
~ound: 497.1699.
T~e following intermediates were prepared or could be prepared by t~e procedure described in Example 209, Part B from the corre6ponding 5-(aminoalkyl)imidazole intermediate and t~e appropriate chloroformate or sulfonyl chloride.
R6 1 N~ R 1 3 3 4 0 9 2 ~ 1 Rl R6 R R MP(C) J~ O
ll ¦ n-butyl Cl CH2NHCOCH2CH3 3 2C ~
~ n-butyl Cl CH2NHCOCH2CH2CH3 " / 3 ll ¦ n-butyl Cl CH2NHCOCH
3 2 \CH3 ~ O
~ n-butyl Cl CH2NHCOCH2CH2CH2CH3 ~ O
ll ¦ n-butyl Cl CH2NHCOC6H5 3 2 ~
~ 0 1I J n-butyl Cl CH2NHCOCH2C6H5 ~ n-butyl Cl CH2-NH-502-CH3 163.0-168.0 234 1 3340~2 PA~T C: Preparation of 2-Butyl-4-chloro-1-t4-(2-carboxybenzoyl)benzyl]-5-(methoxy-carbonYlaminomethyl)imidazole Using the procedure of Example 202, Part C (wit~
or without refluxing), 2-butyl-1-t4-(2-carboxybenzoyl)-benzyl]-g-chloro-S-(methoxycarbonylaminomethyl)imid-azole wa~ prepared from 2-butyl-1-~4-(2-carbomethoxy-benzoyl)benzyl]-4-chloro-5-(methoxycarbonylamino-methyl)imidazole: mp . 6ublime6. NMR (200 MHz, DMS0-d6) ~ 13.17 (bm, lH): 7.97 (d, lH, J~ 7Hz):
7.71 (t, lH, Jz 7Hz): 7.63 (t, lH, J= 7Hz): 7.56 (d, 2H, J= lOHz): 7.50 (m, lH): 7.36 (d, lH, J= 7Hz): 7.03 (d, 2H, J= lOHz): 5.31 (8, 2H): 4.06 (d, 2H, J= 7Hz):
2.46 (t, 2H, J- 7Hz): 1.48 (t of t, 2H, J= 7,7Hz):
1.22 (t of q, 2H, J= 7,7Hz): 0.78 (t, 3H, J~ 7Hz).
Anal. Calcd. for C25H26ClN305: C, 62.05: H, 5.42: N, 8.68. Found: C, 61.97: H, 5.58: N, 8.40. Ma~ Calcd.
for C25H26ClN305: 483.1561. ~ound: 483.1560.
Examples 210-216 in Table 15 were prepared or could be prepared by t~e procedure de6cribed in Example 209, Part C using t~e appropriate ~tarting material.
Table 15 1 3340q2 R61 N~ R8 ~
No. _ R R R MP(C) o "
211 C02H n-butyl Cl CH2NE~COCH2CH2CH3 212 C02H n-butyl Cl CH2NHC-OCH\
"
213 C02H n-butyl Cl CH2NHCCH2CH2CH2CH3 o 214 C02H n-butyl Cl CH2NHCOC6H5 215 C02H n-butyl Cl CH2NHSCH3 (oil)a oo 216 C02H n-butyl Cl CH2NHCOCH2C6H5 a NMR (200 M~z, CDC13) ~ 7.97 (d, lH, J~
7Hz); 7.71-7.50 (m, 4H); 7.45 (d, lH, J=
7Hz); 6.95 (d, 2H, J= 8Hz); 5.23 (6, 2H);
4.15 (~, 2H); 2.57 (t, 2H, J= 7Hz); 1.67 (t of t, 2H, J= 7,7Hz); 1.36 (t o q, 2H, J=
7,7Hz); O.B7 (t, 3H, J= 7Hz).
Example 217 1 3 3 4 0 ~ ~
PART A: Preparation of 2-Butyl~ 4-(2-carbo-methoxybenzoyl)benzyl]-4-chloro-5-[(tri-fluoromethYl6ulfonamido)methyllimidazole Triflic anhydride (0.21 mL, 1.25 mmol, 1.1 eq) was ~lowly added to a pyridine (20 mL) 601ution of the chromium 6alt of 5-aminomethyl-2-butyl-1-[4-(2-carbomethoxybenzoyl)benzyl~-4-chloroimidazole (0.50 g, 1.1 mmol, 1.0 eq) at 0C. The ~olution was allowed to warm to room temperature. After l.S hour, 1.5 equivalent~ of triflic anhydride were added at 0. After an additional 4 hour6 at room temperature, water (200 mL) wa~ added and the pH adjusted to 5.
The aqueou6 was extracted with ethyl acetate (3 x 100 mL) and the organic layers dried (MgSO4) and concentrated to yield 150 mg of a yellow oil which was used as i~ for the subsequent hydrolyci6 ~tep.
NMR (200 MHz, CDC13) ~ 8.33 (bm, lH); 7.96 (d, lH, J= 7Hz); 7.64 (d, 2H, J= 10Hz); 7.56 (t, lH, J=
7Hz); 7.48 (t, lH, J= 7Hz); 7.28 (d, lH, J= 7Hz);
6.92 (d, 2H, J= 10Hz); 5.21 (fi, 2H); 4.14 (~, 2H);
3.17 (6, 3H); 2.48 (t, 2H, J= 7Hz); 1.55 (t of t, 2H, J= 7,7Hz); 1.24 (m, 2H); 0.79 (t, 3H, J= 7Hz).
5 PART B: Preparation of 2-Butyl-l-t4-(2-carboxy-benzoyl)benzyl~-4-chloro-5-t(trifluoro-methylsulfonamido)methYl~imidazole 2-Butyl-l-t4-(2-carbomethoxybenzoyl)ben2yl~-4-chloro-5-t(trifluoromethyl~ulfonamido)methyl~imidazole (150 mg, 0.26 mmol, 1 eq), 1.000 N NaOH (0.55 mL, 0.55 mmol, 2.1 eq), methanol (20 mL), and water (0.5 mL) were mixed and stirred for 5 hour~ at room temperature under N2. The solvent was removed in vacuo. Water (50 mL) was added and the pH was adju6ted to g with 1 N HCl. Tan 601idfi precipitated. The6e were collected and dried to yield 89 mg. NMR (200 MHz, DMSO-d6) ~ 7.98 (d, lH, J= 7Hz); 7.70 (t, lH, J= 7Hz): 7.68 (t, lH, J=
7Hz); 7.63 ld, 2H, J= lOHz): 7.37 (d, lH, J- 7Hz) 7.10 (d, 2H, J= lOHz): 5.34 (s, 2H): 4.20 (s, 2H):
2.50 (t, 2H, J= 7Hz): 1.49 (t of t, 2H, J= 7,7Hz):
1.27 (t of q, 2H, J= 7,7Hz): 0.80 (t, 3H, J= 7Hz). Ma66 calcd. for C24H23C1~3N305S:
557.0999- Pound: 557.0988 Example 218 PART A: Preparation of 2-Butyl-l-t4-(2-carbomethoxy-benzoyl)benzyl]-5-t(4-carbomethory-1,2,3-triazol-1-yl)methyl]-4-chloroimidazole and 2-butyl-1-14-(2-carbomethoYybenzoyl)benzyl]-5-[(5-carbomethoYy-1,2,3-triazol-1-yl)methyl]-4-chloroimidazole 5-Azidomethyl-2-butyl-4-chloro-1-t4-(2-carbo-methoxybenzoyl)benzyl]imidazole (0.50 g, 1.07 mmol, 1 eq), methyl propiolate (0.95 mL, 10.7 mmol, 10 eq) and toluene (20 mL) were mixed and refluxed under N2 for 3 hour6. The reaction mixture wa6 concentrated and the re6idue fla6h chromatographed over silica gel in 75:25 hexane/ethyl acetate. The two regioi60mer6 were separated to give 10 mg of the fa6ter eluting i60mer a6 a gla66 and 330 mg of the 610wer a6 a solid.
The 610wer i60mer could be further purified by wa6hing with ethyl acetate to give 190 mg of white cry6talline 601id. Pa6ter eluting i60mer: NMR (200 MHz, CDC13) 8.06 (d, lH, J= 8Hz) 7.96 (6, lH): 7.73-7.54 (m, 4H):
7.37 (d, lH, J= 8Hz); 6.86 (d, 2H, J= 8Hz): 5.76 (6, 2H); 5.41 (6, 2H); 3.90 (6, 3H): 3.68 (6, 3H): 2.56 (t, 2H, J= 7Hz); 1.67 (t of t, 2H, J= 7,7Hz); 1.35 -(t of q, 2H, J= 7,7Hz); 0.86 (t, 2H, J= 7Hz). Ma66 calcd. for C28H28N505Cl: 549.1778. Found: 549.1860.
Slower eluting isomer: m.p. 163.5-167.0: NMR (200 MHZ, CDC13) ~ 8.06 (d, lH, J= 8Hz); 8.00 (8, lH);
7.72 ~d, 2H, J= 8Hz); 7.72-7.55 (m, 2H); 7.41 (d, lH, J= 7Hz); 6.96 (d, 2H, J= 8Hz); 5.40 (6, 2H); 5.23 (6, 2H); 3.95 (6, 3H); 3.69 (6, 3H~; 2.58 (t, 2H, J= 7Hz);
1.70 (t of t, 2H, J= 7,7Hz): 1.38 (t of q, 2H, J=
7,7Hz); 0.89 (t, 3H, J= 7Hz). Ma66 calcd. for C28H28N5O5Cl: 549.1778. Pound: 549.1763.
The intermediate6 6hown below were prepared or could be prepared by the procedure de6cribed in Example 218, Part A u6ing the appropriate 6tartinq material6, N ~
S ~
~0 ,~1~ R 13 R _ R R MP(C) n-butyl Cl CH2-N ~ N C2CH3 (oll) n-Bu i60mer6) n-butyl Cl CH2 ~ N C2CH3 n-butyl Cl CH2-N N`N NHS02CF3 n-butyl Cl CH2-N ~ N 2 3 co2~
n-butyl Cl CH2-N ~ N 2 3 n-propyl H CH2-N ~ N N 2CF3 Co2cH2c6H5 n-propyl H CH2-N ~N 2 3 -240 1 3~40q 2 a NMR (200 MHz, CDC13) shows a mixture of 2 regioi60mer6: ~ 8.08 (d, lH, J= 8Hz);
7.80-7.55 (m, 4H): 7.44-7.34 (m, lH); 7.28 (s, lH); 7.00-6.88 (m, 2H); 5.40 (6, 0.5 x 2H); 5.32 (6, 0.5 x 4H); 5.29 (6, 0.5 ~ 2H);
3.71 (6, 0.5 x 3H); 3.69 (6, 0.5 ~ 3H);
2.75-2.48 (m, 4H); 1.80-1.21 (m, 8H);
1.00-0.81 (m, 6H).
PART B: Preparation of 2-Butyl-1-~4-(2-carboxy-benzoyl)benzyl]-5-t(4-carboxy-1,2,3-triazol-l-yl)met~yl1-4-chloroimidazole and 2-butyl-1-[4-(2-carboxybenzoyl)benzyl]-5-~(5-carboxy-1,2,3-triazol-1-yl)methyl~-4-chloroimidazole The 610wer eluting i60mer in Example 218, Part A
(190 mg, 0.35 mmol, 1 eq), 0.5 N KOH in methanol (2.76 mL, 1.39 mmol, 4 eq) and 5 mL of water were mixed and refluxed overnight under N2. Water (50 mL) wa6 added and the pH adju6ted to 5. The aqueou6 mixture was extracted with ethyl acetate (3 x 50 mL), the organic fraction6 dried (MgSO4) and concentrated to give a re6idue which wa6 triturated with ether yielding 160 mg of 601id product. NMR (200 MHz, DMSO-d6 + py-d5) ~ 8.20 (d, lH, J= 8Hz): 7.86-7.63 (m, 4H); 7.57 (d, lH, J= 8Hz); 7.43 (6, lH); 7.04 (d, 2H, J= 10Hz); 6.84 (6, 2H); 6.63 (6, 2H); 2.62 (t, 2H, J= 7Hz); 1.65 (t of t, 2H, J= 7,7Hz); 1.30 (t of q, 2H, J= 7,7Hz); 0.81 (t, 3H, J= 7Hz). Ma66 calcd. for C26H24N5O5Cl-CO2:
477.1567. Found: 477.1593.
The fa6ter eluting isomer in Example 218, Part A
was hydrolyzed in a 6imilar fashion except that upon acidification in the work-up, 601id product precipi-tated, m.p. 149.0-152.5. NMR (200 MHz, DMSO-d6) ~
8.02 (6, lH); 8.02 (d, 2H, J= 7Hz); 7.74 (t, lH, J=
7Hz); 7.66 (t, lH, J= 7Hz): 7.50 (d, 2H, J= 7Hz); 7.37 (d, lH, J= 7Hz); 6.92 (d, 2H, J= 7Hz); 5.83 (s, 2H);
5.42 (s, 2H); 2.52 (t, 2H, J= 7Hz): 1.55 (t of t, 2H, J= 7Hz); 1.28 (t of q, 2H, J= 7,7Hz); 0.78 (t, 3H, J=
7Hz). Mass calcd. for C26H2gN505Cl~C02:
477.1567. F~und: 477.1479.
Examples in Table 16 were prepared or could be prepared by the procedure described in Example 218, Part B.
Table 16 N ~
R6 ~ N ~ R8 ~0 ~ R13 No _ R R R MP(C) 219 n-butyl Cl 2 N ~ N C02H (oil) isomers) 220 n-butyl Cl 2 ~ C02H
COOH OOH
221 n-butyl Cl2 ~ NHS02CF3 COOH
222 n-butyl ClCH2 N ~ N NHS02CF3 COO~I
-242 1 3340~2 a NMR (200 MHz, CDC13) ~ 8.03 (m, lH);
7.77-7.42 (m, SH); 7.33 (6, lH); 5.36 (s, 2H); 5.26 (6, 2H); 2.68-2.45 (m, 4H);
1.82-1.48 (m, 4H); 1.42-1.20 (m, 4H):
1.00-0.80 (m, 6H).
Example 223 PART A: Preparation of 1-(4-~ormylbenzyl)-2-butyl-4-chloro-5-hydroxymethylimidazole To a 601ution of 5.05 g of 1-(4-cyanobenzyl)-2-butyl-4-chloro-5-hydroxymethylimidazole in 350 mL of benzene at 25 was added dropwi6e 22.8 mL of dii60-butylaluminum hydride (0.15 M in toluene). The mixture wa6 warmed to 45 and 6tirred for 16 ~our6.
After cooling, the reaction mixture was poured in ice-cold 20% aqueou6 6ulfuric acid. Thi6 601ution wa6 allowed to warm to 25 and then 6tirred for 2 bour6.
The 601ution was cooled to 0, neutralized using aqueous sodium hydroxide and extracted with ethyl acetate. The combined organic phases were wa6hed with water and brine, dried over anhyd{ous sodium 6ulfate, filtered, and concentrated. Column chromatography on silica gel (elution: 0-20% ethyl acetate/benzene) provided 3.60 g of 1-(4-formyl-benzyl)-2-butyl-4-chloro-5-hydroxymethylimidazole; NMR
(200 MHz, CDC13) ~: 9.96 (6, lH); 7.47 (A2M2, 4H);
5.26 (6, 2H); 4.42 (s, 2H); 2.54 (t, 2H); 1.64 (quint., 2H); 1.32 (6ext., 2H); 0.86 (t, 3H).
PART B: Preparation of 1-[(2'-Cyano-trans-6tilben-4-yl)methyl]-2-butyl-4-chloro-5-~ydroxy-methylimidazole To a solution of 0.98 g of a-bromo-o-tolu-nitrile in 25 mL of dimethylformamide at 2~ was added 3s 1.40 g of triphenylphosphine. The mixture was stirred 243 1 3340~2 at 80 for 3 hour6, then treated with 1.53 g of 1-(4-formylbenzyl)-2-butyl-4-chloro-5-hydroxymethylimid-azole, followed immediately by 0.54 g of 60dium methoxide, and the mixture wa6 diluted witb water and extracted with benzene. The organic phase6 were com-bined and wa~ed with water and brine, dried over anhydrous 60diu~ 6u~fate, filtered, and concentrated.
Column chromatograp~y on ~ilica gel (elution: 0-20%
ethyl acetate/benzene) afforded 0.45 ~ of 1-t(2'-cyano-tran6-6tilben-4-yl)methyl~-2-butyl-4-chloro-5-hydroxymethylimidazole; NMR (200 MHz, CDC13):
8.01 (d, lH); 7.85 (d, lH): 7.73 (t, lH); 7.47 (t, lH); 7.44 (AB, 2H, J=16.3); 7.38 (A2B2, 4H); 5.28 (6, 2H); 5.24 (t, lH); 4.34 (d, 2H); 2.49 (t, 2H);
1.47 ~quint., 2H); 1.24 (6ext., 2H): 0.79 (t, 3H).
PART C: l-t(2'-Carboxy-tran6-6tilben-4-yl)methyl]-2-butyl-4-chloro-5-hydroxYmethylimidazole A 601ution of 0.40 g of l-t2'-cyano-tran6-6tilben-4-yl)methyl~-2-butyl-4-chloro-5-hydroxymethyl-imidazole in 20 mL of ethylene glycol and 12 mL of 10%
aqueou6 60dium hydroxide was refluxed for 5.5 hour6.
After cooling, the reaction mixture was filtered, and the 601vent was removed in vacuo. The re6idue wa6 di6solved in water, and the 601ution wa6 acidified to pH 3.5 u6ing hydrochloric acid and the re~ulting emul6ion was extracted ~ith chloroform. The combined organic pha6e6 were wa6hed with saturated aqueou6 60dium chloride ~olution, dried over anhydrou6 60dium sulfate, filtered and concentrated. Column chroma-tography on 6ilica gel (elution:5t methanol/chloroform) afforded 0.12 g of 1-[(2'-carboxy-trans-stilben-4-yl)-methyl]-2-butyl-4-chloro-5-hydroxymethyli~idazole; NMR
(200 MHz, CDC13): ~ 8.08-8.00 (m, 2H); 7.71 (d, lH); 7.57-7.47 (m, 3H); 7.34 (t, lH); 7.01-6.92 (m, 3H); 5.21 (6, 2H); 4.50 (6, 2H); 2.60 (t, 2H); 1.62 (quint, 2H); 1.31 (6ext., 2H); 0.03 (t, 3H).
Example 225 PART A: Preparation of N-(4-Benzyloxybenzyl)glycine ethyl e6ter To a 6uspension of 11.0 g of glycine ethyl e6ter hydrochloride in 100 mL of dimethylformamide at 25 wa6 added 22.0 mL of triethylamine. To the re6ulting milky 6u6pension wa6 added 9.08 g of 4-benzyloxybenzyl chloride in 50 mL of DMF dropwi6e over 0.5 hour. The mixture wa6 6tirred for 16 hour6 at 25. The reaction mixture wa6 diluted with diethyl ether and then fil-tered to remove the precipitated triethylamine bydro-chloride. The re6ulting ~olution wa6 concentrated invacuo, and the re6idue was di6~01ved in ethyl acetate.
The 601ution wa6 wa6hed with water and brine, dried over anhydrous 60dium 6ulfate, filtered, and concen-trated. Kugelrohr di6tillation provided 5.90 q of N-(4-benzyloxybenzyl)glycine ethyl ester tbp 160-180 (0.015 torr.)]; NMR (200 MHz, CDC13): ~ 7.43-7.27 (m, 5H); 7.06 (A2B2, 4H); 5.01 (6, 2H); 4.14 (quart., 2H);
3.71 (s, 2H); 3.36 (6, 3H); 2.01 (bs, lH): 1.24 (t, 3H).
PART B: Preparation of N-(4-Benzyloxybenzyl)-N-formyl-qlycine ethyl ester A 601ution of 5.83 g of N-(4-benzyloxybenzyl)-qlycine ethyl e6ter, 0.86 mL of formic acid, and 20 mL
of xylene was refluxed for 2 hour6 u6ing a Dean-Stark trap to remove the water produced in tbe reaction.
After cooling, t~e reaction mixture was wa6hed with 20~ aqueous formic acid, water, 6aturated 60dium bicarbonate solution, water, and brine. Finally the mixture was dried over anhydrous 60dium 6ulfate, -filtered, and the filtrate wa6 concentrated to furni6h 6.23 g of crude N-(4-benzyloxybenzyl)-N-formyl glycine ethyl e6ter, u6ed in the followinq reaction without further purification.
PART C: Preparation of 1-(4-Benzyloxybenzyl)-5-carbo-methoxy-2-(3H)-imidazolethione To a su6pension of 1.10 g of 60dium methoxide in 35 mL of tetrahydrofuran at 10 there wa6 added in one portion, a 601ution of 6.23 g of N-(S-benzyloxybenzyl)-N-formyl glycine ethyl e6ter and 3.46 mL of methyl formate in 15 mL of TH~. The mixture wa6 6tirred at 10 for 1 hour and then at 25 for 16 hour6. The 601vent wa~ removed in vacuo and t~e re6idue di6601ved in 36 mL of methanol. To thi6 601ution wa6 added 3.57 mL of conc. hydrochloric acid, and the mixture was 6tirred at 40 for 0.5 hour. A 601ution of 2.80 g of pota66ium thiocyanate in 6 mL of water wa6 added, and the re6ultin~ mixture wa6 6tirred for 16 hour6 at 40. Finally, 40 mL of water wa6 added, and the mixture wa6 allowed to cool to 25. The precipitated 601id wa6 recovered by filtration to afford 3.60 g of 1-(4-benzyloxybenzyl)-5-carbomethoxy-2(3H)-imidazole-thione; NMR (200 MHz, CDC13): ~ 11.25 ~b6, lH):
8.05 (6, lH); 7.39 (m, 5H); 7.03 (A2B2, 4H); 5.06 (6, 2H); 4.56 (6, 2H); 3.81 (6, 3H).
PART D: Preparation of 1-(4-Benzyloxybenzyl)-2-propyl-thio-S-carboethoxyimidazole To 60 mL of ethanol at 25 wa6 added portionwise 0.30 g of 60dium metal. After the 60dium metal ha6 reacted 3.54 g of 1-(4-benzyloxybenzyl)-5-carbomethoxy-2-(3H)-imidazolethione wa6 added followed immediately by 2.24 mL of l-iodopropane, and the mixture wa6 6tirred at 24 for 3 hour6. At thi6 point, the 246 1 3~4092 solvent was removed in vacuo, and the residue was dissolved in methylene chloride. This solution was washed with water and brine, dried over anhydrous sodium sulfate, iltered, and concentrated to furnish 3.46 g of crude 1-(4-benzyloxybenzyl)-2-propylthio-5-carboethoxyimidazole, used in a subsequent reaction without further purification: NMR (200 MHz, CDC13):
.77 (s, lH); 7.45-7.32 (m, 5H): 7.03 (A2B2, 4H); 5.49 (s, 2H); 5.03 (s, 2H); 4.28 (quart., 2H):
3.20 (t, 2H); 1.32 (t, 3H); 1.02 (t, 3H).
The following intermediates were prepared or could be prepared employing the above procedure.
~7 N
R6 J~ N ~R8 n-C6H13S- H C02CH2CH3 n-C4HgS- H CO2CH2CH3 0 PART E: Preparation of 1-(4-Benzyloxybenzyl)-2-propyl-thio-5-hydroxymethylimidazole A solution of 2.05 g of 1-(4-benzyloxybenzyl)-2-propylthio-5-carboethoxyimidazole in 10 mL of tetra-hydrofuran was added dropwise to 10 mL of lM lithium 3S aluminum hydride in THF at 0 such that the reaction temperature remained below 5. The resulting solution then was stirred at 0 for 1 hour. At this point, the reaction mixture was quenched by 6equential dropwise addition of 0.40 mL of water, 0.40 mL of 15~ aqueous sodium hydride, and 1.20 mL of water. The resulting suspension was filtered employing diethyl ether, and the filtrate was concent~ated to furnis~ 1.55 g of l-(g-benzyloxybenzyl)-2-propylthio-5-hydroxymethyl- -imidazole; NMR (200 MHz, CDC13): ~ 7.41-7.29 (m, 5H); 7.03-6.86 (m, 5H); 5.22 (s, 2H); 5.01 (s, 2H):
4.45 (s, 2H); 3;01 (t, 2H): 2.32 (bs, lH): 1.66 (sext., 2H); 0.97 (t, 3H).
The intermediates 6hown below were prepared or could be prepared employing the above procedure.
N ,,R
R6~N ~R8 n-C6H13S- 2 n-C4HgS- 2 2q8 PA~T F: Preparation of 1-(4-Hydroxybenzyl)-2-propyl-_thio-5-hydroxy~ethylimidazole A solution of 1.40 g of 1-(4-benzyloxybenzyl)-2-propylthio-5-hydroxymethylimidazole in 15 mL of trifluoroacetic acid was refluxed for 0.25 hour.
After cooling, the reaction was poured into water contain~ng an excess of sodium bicarbonate, and the resulting emulsion was extracted with ethyl acetate.
The combined organic phases were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated. Column chromatography on silica gel (elution: 0-5% methanol/chloroform) afforded 0.28 9 of l-(4-hydroxybenzyl)-2-propylthio-S-hydroxymethyl-imidazole: ~R (200 MHz, DMSO-d6): ~ 9.41 (s, lH); 6.88 (s, lH); 6.79 (A2B2, 4H); 5.14 (t, lH);
5.07 (s, ZH): 4.33 (d, 2H); 2.89 (t, 2H); 1.54 (sext., 2H); 0.88 (t, 3H).
These intermediates were prepared or could be prepared employing the above procedure.
N R
R6l~R8 ~
n-C6H13S- 2 n-CgHgS- 2 249 l 334092 STEP G: Preparation of 1-[4-(2-Cyanobenzyloxy)benzyl]-2-Pro~ylthio-5-hydroxYmethylimidazole The title compound was prepared from 1-(4-hydroxybenzyl)-2-propylthio-5-hydroxymethylimidazole using the procedure described in Example 192, Part C; NMR (200 MHz, CDCl3): ~ 7.66 (m, 3H); 7.43 (m, lH); 7.03 (2, lH); 6.99 (A2B2, 4H); 5.23 (s,2H); 5.22 (s, 2H); 4.47 (s,2H); 3.04 (t, 2H); 1.69 (sext., 2H); 0.98 (t, 3H).
The following 2-mercaptoimidazoles shown below were prepared by the procedure illustrated above.
~ 7 ~ 1~3 x~
X
CN
n-C6Hl3S- H CH2OH 4-OCH
CN
n-C4HgS- H CH2OH 4-OCH
0 STEP H: Preparation of 1-[4-(2-Carboxybenzyloxy)-benzyl]-2-propylthio-5-hydroxymethylimidazole A solution of 0.23 g of 1[4-(2-cyanobenzyloxy)-benzyl]-2-propylthio-5-hydroxymethylimidazole in 17 ml of ethylene glycol and 7 ml of 10~ aqueous sodium hydroxide was refluxed for 14 hours. After cooling, the reaction mixture was filtered, and the solvent was ~, removed in vacuo. The residue was dissolved in water, and the solution was acidified to pH 3.5 using hydrochloric acid. The precipitated solid was recovered by filtration and recrystallized from aqueous ethanol to furnish 0.094 g of 1-[4-(2-carboxybenzyloxy)benzyl]-2-propylthio-5-hydroxymethylimidazole; NMR (200 MHz, DMS0-d6); ~ 13.12 (bs, lH); 7.93 (d, lH); 7.58 (m, 2H); 7.45 (m, lH); 6.99 (A2B2, 4H);
p 6.98 (s, lH); 5.42 (s, 2H); 5.25 (bs, lH); 5.17 (s, 2H); 4.35 (s, 2H); 2.92 (t, 2H); 1.54 (sext., 2H); 0.89 (t, 3H).
The following 2-mercaptoimidazoles of Table 17 were prepared or could be prepared by the procedure illustrated above.
Table 17 R6 ~ N ~ R8 ~R13 Ex. x ~ 13 NO. R6 R7 R8 n-c6H135- H CH20H 4-0CH2 _~
Co2H
226 n-C4H95- H CH20H 4-OCH
X
.
Example 227 PART A: ~reparation of 1-(4-Nitrobenzyl)-2-butyl-4-chloroimidazole-5-aldehyde A mixture of 1 g of 1-(4-nitrobenzyl)-2-butyl-4-chloro-5-hydroxymethyl imidazole and 5 g of activated MnO2 in CH2C12 wa6 6tirred at room temperature for 16 hour6. The reaction mixture wa6 filtered through celite and the filtrate wa6 concentrated to give a thick oil which wa6 purified by fla6h column chroma-tography on 6ilica gel (Hexane:ethyl acetate=1.5:1 elution). The de6ired compound was obtained as a colorle66 solid, 0.76 g: m.p. 88-89; NMR (200 MHz, CDC13): ~ 9.74 (2, lH); 5.64 (s, 2H); 2.63 (t, 3H, J=7.4 Hz); 1.68 (m, 2H); 1.34 (m, 2H): 0.89 (t, 3H, J=7.3 Hz).
PART B: Preparation of 3-tl-(4-Nitrobenzyl)-2-butyl-4-chloroimidazol-S-yl~propenoic acid, ethyl e6ter, E and Z i60mer6 A mixture of 1.2 g of 1-(4-nitrobenzyl)-2-butyl-4-chloroimidazole-5-aldehyde and 1.5 g of (carboxy-methylene)triphenylpho6phorane in 50 mL of benzene was refluxed for 2 hours. The reaction mixture wa6 concentrated and the re6idue wa6 purified by fla6h column chromatography on 6ilica gel (Hexane:EtOAc=3:1 elution). The major product, the E i60mer, wa~ eluted first and wa6 obtained a6 a thick oil initially which solidified to give an amorphou6 601id, 1.2 g. The minor product, the Z i60mer was eluted next and wa6 i601ated as a thick liquid, 85 mg. E i60mer: NMR
(200 MHz, CDC13): 7.3 and 6.53 (d, 2H, 5=16 Hz):
5.3 (s, 2H); 2.62 (t, 2H, J=7.3 Hz); 1.69 (m, 2H);
1.28 (m, 5H); 0.89 (t, 3H, J=7.3 Hz).
Z isomer: NMR (200 MHz, CDC13): (key peaks only) ~ 6.45 and 6.02 (d, 2H, J=11.8 Hz); 5.17 (s, 2H).
`~ 252 1 3340~2 PART C: Preparation of 3~ (4-Nitrobenzyl)-2-butyl-4-chloroimidazol-5-Yllpropen-l-ol~ E i60mer A 601ution of 0.5 g of 3-11-(4-nitrobenzyl)-2-butyl-4-chloroimidazol-5-yl]propenoic acid, ethyl e6ter, E isomer in 20 mL of TH~ wa~ cooled with an ice batb, 1.7 mL of 1.5 M dii60propylaluminum hydride (in toluene) wa6 added 610wly. The cooling bath wa6 removed and the reaction ~ixture wa6 6.tirred at room temperature for 1 hour. The reaction mixture wa6 then guenched with 3 mL of conc. NH~Cl ~oluti~n and the mixture wa6 6tirred for an additional 30 minute6.
During thi~ period an exten6ive gel~ e ~aterial formed. The reaction mixture wa6 further diluted with ether and filtered through Celite*. ~he filtrate wa6 concentrated and the crude product wa6 purif~ed by fla~h column chromatography on 6ilica gel (Hexane:
EtOAc~l:l elution). The de~ired co~pound wa6 obtained a6 a thic~ liguid; NMR (200 MHz, CDC13): ~ 6.5-6.15 (m, 2H): 5.21 (6, 2H): 4.25 (d, 2H, J.4.5 Hz): 2.35 (t, 3H, J~7.4 Hz): 1.68 (m, 2H): 1.34 (m, 2H): 0.86 (t, 3H, J=7.4 Hz).
PART D: Preparation of 3-tl-(4-Aminobenzyl)-2-butyl-4-chloroimidazol-5-Yl~propen-l-ol~ ~ i60mer A mixture of 0.2 g of 3-~1-(4-nitrobenzyl)-2-butyl-4-chloroimidazol-5-yl]propen-1-ol, 0.15 g of iron and 0.3 mL of glacial acetic acid in 10 mL of ab~olute ethanol wa6 refluxed for 1 bour. The reac-tion mixture wa6 concentrated to dryne66 and the re6idue wa6 di6601ved in 20 mL of water and the 601u-tion wa6 made basic to pH 8 by adding ~2C03. The mixture was then extracted with ethyl acetate and the ethyl acetate layer was wa6hed with water. The organic layer was concentrated to give a crude product wbich wa~ purified by flash 6ilica gel column chromatography * trade mark 1 3340~2 (ethyl acetate elution). A pure product was obtained as an amorphou6 solid; NMR (200 MHz, CDC13): ~ 6.76 and 6.62 (dd, 4H, J=8.5 Hz); 6.42-6.22 (m, 2H); 2.57 (t, 2H, J=7.3 Hz), 1.65 (m, 2H); 1.33 (m, 2H); 0.87 5 (t, 2H, J=7.3 Hz).
PART F: Preparation of 3-~1-(4-(2-Carboxybenzamido)-benzyl)-2-butyl-4-chloroimidazol-5-yl]-Propen-l-ol~ E isomer To a solution of 95 mg Of 3-tl-(4-aminobenzYl)-2-butyl-4-chloroimidazol-5-yl]propen-1-ol in 2 mL of CHC13 wa~ added 45 mg of phthalic anhydride and the mixture was stirred at room temperature for 1 hour.
During thi6 period of time the initially clear 601u-tion became turbid and produced ~olid. The reaction mixture was diluted wit~ 2 mL of ether and the solid wa6 collected by filtration and washed with ether.
The desired product was obtained as a tan solid, 115 mg, m.p. 150-151; NMR (10~ DMS0-d6/CDC13): ~ 9.94 (5. lH); 7.71 and 6.93 (d, 4H, J=8.3 Hz); 6.36 (m, 2H); 5.1 (s, 2H); 4.18 (d, 2H, J=3.9 Hz); 2.6 (t, 3H, J=7.4 Hz): 1.68 (m, 2H): 1.34 (m, 2H): 0.89 (t, 3H, J=7.4 Hz).
ExamPle 228 PART A: Preparation of 3-t2-Butyl-4-chloro-1-(4-aminobenzyl)imidazol-5-yl]propenoic acid ethYl e6ter, E i60mer A mixture of 0.5 g of 3-t2-butyl-4-chloro-1-(4-nitrobenzyl)imidazol-5-yl]propenoic acid et~yl ester (E isomer) prepared from Part B of Example 227, 1 g of iron and 2 mL of glacial acetic acid in 30 mL of absolute ethanol was refluxed for 1 hour. The reac-tion mixture was concentrated to dryness and the residue was dis601ved in 50 mL of H20. The aqueous 601ution wa6 adju6ted to pH 8 by K2C03 and was extracted witb ethyl acetate. Tbe crude product obtained upon concentration of tbe etbyl acetate extract was purified by flash 6ilica gel column chromatography (hexane:ethyl acetate.l:l elution).
The de6ired compound was obtained as a thic~ colorless oil, 0.35 g.
PART B: Preparation Of 3-t2-Butyl-4-chloro-1-(~-(2-carboxybenzamido)benzyl)imida201-S-yl~-ProPenoiC acid etbyl ester, E isomer A mixture of 361 Dg of the aniline derivative obtained from Part A and 150 mg of phthalic anhydride in 3 mL of chloroform was 6tirred at room temperature for 1 hour. The reaction ~ixture was concentrated and tbe residue was triturated iD ethyl ether. The resulting 601id wa6 collected and dried to give a colorless 601id, 450 mg, m.p. 180-181. NMR (CDC13, 5~ DMS0-d6) ~ 0.91 (t, 3H, J~ 7,1Hz): 1.1-1.4 (m, 5H): 1.60 (q, 2H, J~ 7,3Hz): 2.71 (t, 2H, J. 8,4Hz):
4.17 (q, 2H, J~ 7,3Hz); 5.23 (6, 2H): 6.46 ~ 7.38 (d each, 2H, J. 16,1Hz): 6.0-8.0 (m, 8H), 10.2 (6, lH).
ExamPle 229 PART A: Preparation of 1-(2'-Carbomethoxybi-phenyl-4-yl)metbyl-2-butyl-4-chloro-imidazole-5-carboxaldebyde A mixture of 0.68 g of the ~ydroxymethyl precursor prepared in Example 85, Part C and 3.4 q of activated MnO2 in 30 mL of CHC13 wa6 6tirred at room temperature for 4 hours. Tbe reactioD mixture was then filtered through Celite and the filtrate wa6 concentrated to give a thic~ oily residue which was purified by flash chromatograpby on silica gel (hexane:ethyl acetate=2:1 elution). Tbe de6ired ,, 1 3340~2 aldehyde was obtained as a thic~ colorles6 oil, 0.5 q NMR (CDC13): 9.78 (6, lH); 5.6 (8, 2H): 3.63 (6, 3H); 2.63 (t, 3H, J=7.4 Hz); 1.68 (m, 2H): 1.34 (m, 2H); 0.89 (t, 3H, J=7.4 Hz).
PART B: 4-tl-(2'-Carbomethoxybiphenyl-4-yl)methyl-2-butyl-4-chloroimidazol-5-yl]-3-buten-2-one, E isomer A mixture of 0.5 g of 1-(2'-carbomethoxybi-phenyl-4-yl)methyl-2-butyl-4-chloroiDidazole-5-carboxaldehyde and .04 g of l-triphenylpho6phoran-ylidene-2-propanone in 20 mL of benzene wa6 refluxed for 16 hour6. The reaction misture was concentrated to give an oily re6idue whic~ wa6 purified by fla6h chromatography on 6ilica gel (hexane:ethyl acetate.l:l elution). The de6ired compound va6 obtained a6 a thick yellowi6h liquid, 0.46 g: NMR (200 MHz, CDC13):
7.9-6.8 (m, lOH): 5.24 (6, 2H): 3.62 (6, 3H): 3.62 (6, 3H): 2.69 (t, 2H, J=7.4 Hz): 2.26 (6, 3H): 1.72 (m, 2H): 1.38 (m, 2H): 0.91 (t, 3H, J=7.4 Hz).
PART C: Preparation of 4-tl-(2'-Carbomethoxybi-phenyl-4-yl)metbyl-2-butyl-4-chloro-imidazol-5-Yl]-3-buten-2-ol~ ~ i60mer A 601ution of 0.45 g of the compound prepared in Part B in 5 mL of methanol was cooled with ice and 0.2 g of NaBH4 wa6 added portionwi6e. After all the NaBH4 wa6 added the reaction mixture wa6 6tirred for 10 minute6. The reaction mixture wa6 concentrated to dryne66 and the re6idue wa6 treated with 3 mL of 6atd.
NH4Cl and the mixture wa6 6tirred at room temperature for 10 min. The mixture wa6 then extracted with ethyl acetate and the ethyl acetate extract was concentrated t~ give a thick liquid, 0.45 g; NMR (200 MHz, CDC13):
6.45-6.15 (m, 2H,): 5.16 (6, 2H); 4.34 (m, lH, ): 3.67 (8, 3H).
Example 230 PART A: Preparation of 1-(4-nitrobenzyl)-2-butyl-4-chloro-5-(2-phenylethen-1-yl)imidazole, E i60mer A colution of 0.4 g of benzyltriphenylpho6-phonium chloride in 20 mL of dried THF wa6 cooled to -30. To the above solution wa6 added 0.65 mL of 1.6 M n-BuLi dropwi6e. A6 the BuLi wa6 added the colution turned to deep orange color. After 6tirring for 10 min. at -30, 0.32 ~ of 1-(g-nitrobenzyl)-2-butyl-4-chloroimidazole-S-aldehyde wa6 added and the reaction mixture wa6 allowed to warm up to room temperature and 6tirred at room temperature for 2 hour6. The reaction mixture wa6 guenched with 2 ~L of 6aturated NH4Cl solution and diluted with ethyl acetate, and the etbyl acetate 601ution wa~ wa6hed with water and a brine 601ution. Evaporation gave a thic~ oily re6idue which wa6 purified by the fla6h ~ilica gel column chroma-tography (hexane:ethyl acetates3:1 elution) to give a thick yellow oil, 0.39 g, PART B: Preparation of l-t4-(2-Carboxybenzamido)-benzyl]-2-butyl-4-chloro-5-(2-phenylethen-l-yl~imidazole, E i60mer The compound wa6 prepared from the compound of Part A by the procedure de6cribed in Example 227, Part6 D and E; m.p. 111-113 (dec).
ExamPle 231 PART A: Preparation of 3-12-Butyl-4-chloro-1-(4-nitrobenzyl)imidazol-5-yl]-3-propen-1-ol acetate, E i~omer A mixture of 1 g of 3-tl-(4-nitrobenzyl)-2-butyl-4-chloroimidazol-5-yl]propen-1-ol obtained from Part C
of Example 227, 1 mL of acetic anhydride and 2 mL of pyridine in 20 mL of CH2C12 was stirred at room temperature for 16 hours. The reaction mixture was diluted with 100 mL of ethyl acetate and the organic layer was washed with H20. T~e crude product obtained upon concentration of the organic layer was purified by flash silica gel chromatography (hexane:
ethyl acetate=l:l elution) to give the desired acetate as a thick colorless oil, O.9S g.
0 PART B: Preparation of 3-~2-Butyl-4-chloro-1-(4-aminobenzyl)imidazol-5-yl]-3-propen-1-ol acetate, E isomer The nitro compound obtained from Part A was reduced to t~e amino compound by the conditions described in Part D of Example 227. The desired compound wa6 obtained as a colorles~ thic~ oil.
PART C: Preparation of 3-t2-Butyl-4-chloro-1-(4-(2-carboxybenzamido)benzyl)imidazol-S-yl]-3-propen-l-ol acetate, E isomer The phthalamic acid derivative was obtained from the aniline derivative obtained from Part B and phthalic anhydride by the method described in Part E
of Example 227. The desired compound was obtained as a colorless solid, m.p. 84-87.
NMR (CDC13) ~ 0.91 (t, 3H, J= 7,1Hz); 1.2 (m, 2H); 1.7 (m, 2H); 2.0 (s, 3H); 2.7 (t, 2H, J= 7,4Hz); 4.57 (d, 2H, J= 5,4Hz); 5.06 (s, 2H);
6.24 (m, 2H); 6.9-8.0 (m, 8H); 8.8 (s, lH).
Example 232 Preparation of 3-tl-(4-((N-Trifluoromethane6ulfonyl)-anthranilamido)benzyl)-2-butyl-4-chloroimidazol-5-yl]-3-propen-1-ol acetate, E i60mer A mixture of 0.72 g of 3-t2-butyl-4-chloro-1-(4-aminobenzyl)imidazol-5-yl]-3-propen-1-ol acetate obtained from Example 231, Part B and 0.6 mL of tri-ethylamine in 20 mL of CH2C12 wa6 cooled with an ice bath. To thi6 solution was added 0.6 g of o-(tri-fluoromethane6ulfonamido)benzoyl chloride dropwi6e and the reaction mixture wa6 stirred at room temperature for 2 hour6. The reaction mixture wa6 then diluted with 100 mL of ethyl acetate, and the ethyl acetate 601ution wa6 wa6hed with vater, dried over Na2S04 and concentrated to qive a crude product which wa6 purified by a fla6h silica gel column chromatography (3% aceto-nitrile in ethyl acetate) to give the desired compound a6 a 601id, 1.05 g, m.p. 156-158; NMR (200 mHz, CDC13): ~ 12.9 (bs, lH); 8.12-6.91 (m); 6.3 (8);
5.09 (6); 4.61 (d, 2H, J=4.5 Hz); 2.04 (6, 3H).
ExamPle 233 Preparation of 3-tl-(4-((N-trifluoromethane6ulfonyl)-anthranilamido)benzyl)-2-butyl-4-chloroimidazol-5-yl]-Propen-l-ol~ E i60mer A mixture of 0.9 g of the compound of Example 232 and 3 mL of lN NaOH in 6 mL of metbanol wa6 6tirred at room temperature for 16 hour6. The reaction mixture was diluted with 50 mL of water and the aqueou6 601u-tion wa6 acidified to a pH of 3 with lN HCl to produceextensi~e solids which were collected and wa6hed with water. The 601id6 were then dried in vacuo to give O.85 g of the de6ired product, m.p. 129-131; NMR (200 MHz, 5% DMSO-d6/CDC13): ~ 11.15 (bs, lH); 8.02-6.95 (m, 8H); 6.5-6.3 (m, 2H); 5.13 (6, 2H); 4.19 (d, 2H, J=3.5 Hz).
-Example 234 1 3340~2 PART A: Preparation of 3-t2-Butyl-4-chloro-1-(4-nitrobenzyl)imidazol-5-yl]-2-(carboethoxy)-propanoic acid, ethyl ester The 60dium salt of diethyl malonate wa6 generated from 2.5 g of NaH (50% oil di6per6ion) and 8 mL of diethyl malonate in 100 mL of dried DMP with ice cooling. To the above 601ution wa6 added 5 g of the chloromethyl compound and the mixture wa6 6tirred at room temperature for 3 hours. The reaction mixture was 6tirred at room temperature for 3 hours. The reaction mixture was concentrated and the re6idue wa6 diluted with 100 mL of water. The aqueous layer was acidified to a pH of 6 by lN HCl and the product wa6 extracted with ethyl acetate. The crude product was purified by column chromatography'(Hexane:EtOAc=2:1 elution) which afforded the product a6 a thic~ yellow oil, 2.8 g.
PART B: Preparation of 3-t2-Butyl-4-chloro-1-(4-nitro-benzyl)imidazol-5-yl]propanoic acid methyl e6ter A mixture of 0.5 g of the compound from Part A
in 20 mL of 3N HCl wa6 refluxed for 2 hours. The reaction mixture was cooled and neutralized to a pH of 6 with 4N NaOH 601ution. The re6ulting gummy 601id6 were extracted into ethyl acetate and concentrated to give a thic~ yellow oil, 0.5 g. The propionic acid derivative wa6 di6solved in ethyl ether and was treated with diazomethane in ethyl ether to give a crude methyl e6ter which was purified by column chromatography (hexane:ethyl acetate=l:l) which afforded the product as a waxy 601id, 0.34 g.
-1 3S40~2 PART C: Preparation of 3-t2-Butyl-4-chloro-1-(4-(2-carboxybenzamido)benzyl)imidazol-5-yl]-propanoic acid methyl ester The nitro compound of Part B was reduced to the corresponding amino compound by methods previou61y described. A mixture of 17 mg of the amino compound and 7.5 g of phthalic anhydride in 1 mL of CHC13 was 6tirred at room temperature for 1 hour. The reaction mixture was concentrated to drynes6 and the residue was triturated with ether. The re~ulting 601id6 were collected and wa6hed with ether. The pure product was obtained as a colorles6 solid, 20 mg, m.p. 150.5-151.5 (dec.).
Example 235 Preparation of 3-t2-Butyl-4-chloro-1-(4-((N-trifluoro-methanesulfonyl)anthranilamido)benzyl)imidazol-5-yl~-propanoic acid methyl e~ter Reaction between the amino compound of Example 234, Part C and o-(trifluoromethanesulfonamido)benzoyl chloride using the conditions described in Example 232 produced the title compound as a 601id, m.p. 168-172.
ExamPle 225 PART A: Preparation of 3-11-(4-Nitrobenzyl)-2-butyl-4-chloroimidazol-S-yl]propanoic acid, N~N-dimethylamide To a 601ution of 0.7 g of propionic acid from Part B of Example 234 in 20 mL of methylene chloride was added 0.5 mL of pyridine, 0.16 q of dimethylamine HCl salt and 0.42 g of dicyclohexylcarbodiimide. The mixture was then stirred at room temperature for 16 hours. At the end of the reaction the mixture was filtered through celite and the filtrate wa6 concen-trated to give a thick oily product. Thus obtained -261 1 3340~2 crude product was purified by fla6h column chroma-tography (100% elution) to give a pure product a~ a thick colorle~s oil, 0.68 g; NMR (200 MHz, CDC13) 2.89 (~, 3H): 2.93 (8, 3H); 5.43 (6, 2H).
PART B: Preparation of 3-tl-(4-AminobenZyl)-2-butyl-4-chloroimidazol-5-yl~propanoic acid, N,N-dimethYlamide T~e nitro compound from Part A wa6 reduced by the 6ame method de6cribed in Part D of ~xample 227 to give the amino compound a6 a 601id, m.p. lq6-148.
PART C: Preparation of 3-12-Butyl-4-chloro-1-(4-((N-trifluoromethane 6ul fonyl)ant~ranilamido)-lS benzyl)imidazol-5-yl]propanoic acid, N,N-dimetbYlamine amide The amino compound from Part B wa6 treated with o-(trifluoromethanesulfonamido)benzoyl chloride a6 de~cribed in Example 232 to give the trifluoromethyl-6ulfonamide product, m.p. 106-108.
- PART D: Preparation of 3-t2-Butyl-4-chloro-1-(4-(2-carboxybenzamido)benzyl)imidazol-5-yl]-propanoic acid, N,N-dimethYlamine amide The amino compound from Part B wa6 reacted with phthalic anhydride a6 de6cribed in Part E of Example 227 to give the phthalamic acid derivative, m.p.
139-lq2 .
262 1 3~4092 Example 237 PART A: Preparation of 3-tl-(4-Nitrobenzyl-2-bUtyl-4-chloroimidazol-5-yl]-2-carboethoxy-2-methylproPanoic acid; ethYl ester A 601ution of 2 g of the malonate derivative obtained from Part A of Example 234 in 10 mL of dried DMF was cooled ~ith ice. To the 601ution was added 0.22 g of Na~ (50% oil disper6ion) and the 601ution was stirred for 5 minutes before adding 0.3 mL of methyl iodide. The reaction mixture then stirred at room temperature for 2 hours. The reaction mixture wa6 diluted with 400 mL of ethyl acetate and the organic layer was wa~hed with H20 and brine. The crude product obtained upon concentration of t~e organic layer was purified by flash 6ilica gel column chromatography (hexane:ethyl acetate=l:l elution) to give a pure compound a6 a thic~ colorles6 oil, 1.8 g.
PART B: Preparation of 3-[1-(4-Nitrobenzyl)-2-butyl-4-chloroimidazol-5-Yl~-2-methylpropanoic acid The malonate derivative from Part A was 6ub-jected to the hydrolysi6-decarboxylation condition as described in Part B of Example 234. The desired compound was obtained as a thic~ yellowish liquid.
PART C: Preparation of 3-tl-(4-Nitrobenzyl)-2-butyl-4-chloroimidazol-5-yl~-2-methylpropanoic acid, isoPropyl ester A mixture of 0.38 g of the acid from Part B, 1 mL of isopropyl alcohol and 0.22 g of dicyclohexyl-carbodiimide in 10 mL of ÇH2C12 was stirred at room temperature for 16 hours. The reaction mixture wa6 concentrated and the re6idue was taken into ethyl acetate. Insoluble material was filtered off and the filtrate was concentrated to give a crude product which -was purified by column chromatography (hexane et~yl acetate=2:1 elution) to give the desired compound as a thick colorle~6 oil, 0.36 q.
PART D: Preparation of 3-tl-(9-((N-trifluoromethane-6ulfonyl)anthranilamido)benzyl)-2-methyl-Propanoic acid, isoPropyl ester Tbe title compound wa6 prepared from tbe e~ter of Part C by the metbod6 described ~n Part6 8 and C of Example 236; m.p. 132-135.
ExamPles 238 and 239 PART A: Preparation of d and 1 3-tl-(4-Nitrobenzyl)-2-butyl-4-cbloroimidazol-5-yl]-2-methyl-proPanoic acid, d-(+)-a-methYlbenzylamide A mixture of 0.71 g of tbe propionic acid derivati~e from Part B of Example 237, 0.25 ~L of d-(+)-a-metbylbenzylamine and 0.4 g of dicyclo~exyl-carbodiimide in 50 mL of CH2C12 wa6 6tirred at room temperature for 16 hours. The reaction mixture was concentrated and residue was di~601ved in 100 mL of etbyl acetate. Insoluble material wa6 filtered off tbrougb Celite and t~e filtrate was concentrated to give a crude product wbich was purified by 6ilica qel column chromatography (hexane:etbyl acetate.2:1 elution). Two dia6tereoisomers were separated as a tbick colorle~s oil, 0.37 q eacb.
PART B: Preparation of d and 1 3-tl-(4-Aminobenzyl) 2-butyl-4-cbloroimidazol-5-yl~-2-metbyl-proPanoic acid, d-(~-a-metbYlben2ylamide Tbe nitro compound from Part A was reduced by the ~ame method de6cribed in Part D of Example 227 to give tbe amino compound a~ a tbick colorle66 oil.
:~`
264 1 3340~2 PART C: Preparation of d and 1 3-tl-(4-(2-Carboxy-benzamido)benzyl-2-butyl-4-chloroimidazol-5-yl]-2-methylpropanoic acid, d-(~)-a-methylbenzYlamide Each dia6teroisomer of the amino compound from Part B wa6 reacted with phthalic anbydride separately as de6cribed in Part E of Example 227, to give the phthalamic acid derivative6, ~.p. 188-189.5 and 201-202, respectiYely.
ExamPle 240 Preparation of 1-[(2'-Carboxybiphenyl-4-yl)methyl~-2-butyl-4-chloroimidazole-5-carboxylic acid - To a ~olution of 1.03 g of 1-t(2'-carbomethoxy-biphenyl-4-yl)methyl~-2-butyl-4-chloro-5-hydroxymethyl-imidazole in 10 mL of anhydrous acetic acid at 25 wa6 added a 601ution of 0.62 ~ of chromium trioxide in 10 mL of water. The mixture wa6 stirred at 25 for 15 minute6 and then poured into water. The precipitated 601ids were recovered by filtration and then di6601ved in 50 mL of 1.0 N aqueous 60dium hydroxide 601ution.
The alkaline 601ution wa6 allowed to 6tand at 25 overnight and then wa6 acidified to pH 3 with 10%
aqueou6 hydrochloric acid. The precipitated 601id was recovered by filtration and recry6tallized from ethyl acetate to afford 0.10 g of 1-t(2~-carboxybiphenyl-4-yl)methyl]-2-butyl-4-chloroimidazole-5-carboxylic acid (m.p. 186-187 (decomp.)). NMR (DMSO-d6) ~ 12.97 (br 6, 2H): 7.68 (d, lH): 7.53 (t, lH): 7.41 (t, lH): 7.34 (d, lH): 7.28 (d, 2H): 7.02 (d, 2H): 5.61 (8, 2H):
2.60 (t, 2H): 1.53 (guint.-, 2H): 1.27 (sext., 2H):
0.81 (t, 3H).
Examples 241-264 were prepared u6ing procedures illustrated in Examples 227-240.
Table 18 ~ 3340~
~7 6 ~r ~ 8 ~ 13 ~o. R6 R~ R8 R13 ~P(-C) 241 n-butyl Cl 2 4-~HCo ~ 115-120 242 n-butyl Cl ~C02CH3 ~-~HC ~ 1~1.5-1~2.5 243 n-butyl Cl ~ CH3 ~-~HC ~ 160-162 H
244 n-butyl Cl (CH2)2COCH3 4-HHC0 ~ 164-162 245 n-propyl Cl CH2CH2C02CH3 4-~HC0 246 n-butyl Cl CH2CH(CH3)C2CH(CH3)2 4-UHC0 ~ 123-125 247 n-butyl Cl (CH2)30~c 4-~HC0 ~ 124-127 Table 18 (continued) 1 3 3 4 0 9 2 Ex.
No. R6 R7 R3 R13 MP(C) 248 n-butyl C1 (CH2)30Ac4-NHC0 ~ 64-67 249 n-butyl C1 CH CH C N ~ 0 4 NHC0 ~ 142-144 250 n-butyl Cl CH2CH2C- ~ 0 4-NHC0 ~ 63-64.5 H
251 n-butyl Cl CH20CNHCH34-NHC0 H0zC
~=N\
N NH (amorpho~s Z5Z n-butyl Cl COzH ~ solid) 253 n-pentyl H C0zH 4 ~
254 n-propyl H CHzCH2C-N ~ 0 4 255 n-propyl Cl `_~CH20H 4 256 n-propyl Cl ~ CHzOH 4 ~r T~hl e 18 (continued) l 3 3 4 0 9 2 No. Bh gl R8 B~ MP (C) 257 n-butyl Cl ~~C~ 4-NHCo~3 258 n-butyl Cl ~CCHz~ 4-NHCo~3 CF3S02Nh 259 n-butyl Cl (cH2)2cNHc6H5 4-NHCO~
CF3SO2Nh 260 n-butyl Cl CH2CH2C-N~N-CH3 4-NHCO~
/~ C~H
261 n-butyl Cl CH2CH2C N~
2 62 n-butyl Cl CH2CH2C-N NH 4-~
CF3S02Nh 263 n-butyl Cl CH2CH2C N N-C6H5 4-~
O CF3so2Nh 2 6 4 n -but y l C l CH2 CH2 C02H )=\ 7 5 - 7 6 . 5 4-Q .D
~?-~-.
. .
268 1 3~40q 2 Table 18 (continued) N R R7 R8 R13 MP(C) -_ _ C02~
265 n-butyl Cl CH2CH2CH2CO2H 4 ~ 83-85 Example 210 PART A: Preparation of 2-(But-l-en-l-yl)-5-t-butyldimethylsilyloxymethyl-l-t(2'-carbo-methoxybiphenyl-4-yl)methyl~-4-chloroimidazole 2-(But-l-en-l-yl)-l-t(2'-carbomethoxybi-phenyl-4-yl)methyl]-4-chloro-5-(hydroxymethyl)-imidazole (1.4 9), t-butyldimethylsilyl chloride (0.55 g), and imidazole (0.5 9) were mixed and 6tirred in DMF (5 mL) for 18 hour6 at room temperature. Dilution with ethyl acetate and washing the organic phase with water followed by drying (MgSO4), evaporation of the solvent in vacuo, and flash chromatography in 3:1 hexane/ethyl acetate yielded 1.5 g of a clear oil. NMR (200 MHz, CDC13) ~ 7.83 (d, lH); 7.52 (t, lH): 7.40 (t, lH);
7.33-7.24 (m, 3H); 7.08 (d, 2H); 6.83 (d of t, lH);
6.13 (d, lH); 5.30 (s, 2H); 4.57 (6, 2H); 3.64 (6, 3H); 2.21 (quint., 2H); 1.04 (t, 3H); 0.86 (s, 9H);
0.05 (s, 6H).
0 PART B: Preparation of 5-t-Butyldimethylsilyloxy-methyl-l-t(2'-carbomethoxybiphenyl-4-yl)-methyl]-4-chloroimidazole-2-carboxaldehyde 2-(But-l-en-l-yl)-5-(t-butyldimethyl6ilyloxy-methyl)-l-[(2-carbomethoxybiphenyl-4-yl)methyl-4-chlorimidazole (262 mg) was reacted with osmium tetroxide and sodium periodate by the procedure described in Example 178, Part B for 1.5 hours at room temperature. Work-up and flash chromatography in 3:1 hexane/ethyl acetate yielded 200 mg of an amorphous 601id. NMR (200 MHz, CDC13) ~ 9.74 (~, lH): 7.84 (d, lH), 7.54 (t, lH), 7.43 (t, lH), 7.34-7.25 (m, 3H), 7.16 (d, 2H) 5.83 (6, 2H), 4.65 (s, 2H), 3.64 (6, 3H), 0.90 (6, 9H), 0.09 (6, 6H).
PART C: Preparation of 5-t-Butyldimethyl6ilyloxy-methyl-l-t(2'-carbomethoxybiphenyl-4-yl)-methyl]-4-chloro-2-(cis-pent-1-en-1-yl)-imidazole 5-t-Butyldimethylsilyloxymethyl-l-t(2'-carbomethoxybiphenyl-4-yl)methyl]-4-chloroimidazole-2-carboxaldehyde (200 mg) was added all at once to a solution of n-butyltriphenylphosphonium bromide (0.26 g) and potassium t-butoxide (70 mg) in THF at 0C.
The reaction mixture was stirred at room temperature for 15 minutes when it was quenched with 6aturated aqueous ammonium chloride solution. The mixture wa~
extracted with ethyl acetate, the organic layer6 washed with water, dried (MgS04) and the 601vent removed ln vacuo. The re~idue was flash chromatographed in hexane/ethyl acetate (5:1) to yield 100 mg of an oil. NMR (200 MHz, CDC13) ~
7.85 (d, lH), 7.54 (t, lH), 7.42 (t, lH), 7.35-7.24 (m, 3H), 7.07 (d, 2H), 6.07 (d, lH), 5.87 (d of t, lH), 5.28 (s, 2H), 4.59 (s, 2H), 3.64 (6, 3H), 2.69 (quart., 2H), 1.46 (sext., 2H), 0.91 (t, 3H), 0.86 (s, 9H), 0.05 (s, 6H).
270 1 3340~2 PART D: Preparation of l-t(2'-Carbomethoxybiphenyl-4-yl)methyl~-4-chloro-5-hydroxymethyl-2-(ci6-pent-l-en-l-yl)imidazole 5-t-Butyldimethyl6ilyloxymethyl-l-~(2'-carbo-methoxybiphenyl-4-yl)methyll-4-chloro-2-(ci6-pent-l-en-l-yl)imidazole (100 mg) wa6 de6ilylated vith fluoride by procedure6 familiar to one 6killed in the art. ~la6h chromatography in 1:1 hexaneJethyl acetate yielded 65 mg of a viscou6, colorle66 oil.
NMR (200 MHz, CDC13) ~ 7.85 (d, lH), 7.55 (t, lH), 7.42 (t, lH), 7.28 (m, 3H), 7.05 (d, ZH), 6.11 (d, lH), 5.92 (d of t, lH), 5.30 (6, 2H), 4.57 (d, 2H), 3.64 (6, 3H), 2.69 (guart., 2H), 1.62 (t, lH), 1.47 (6ext., 2H), 0.92 (t, lH).
PART E: Preparation of l-t(2-Carboxybiphenyl-4-yl)-methyl]-4-chloro-5-hydroxymethyl-2-(ci6-Pent-l-en-l-yl)imidazole l-t2~-Carbomethoxybiphenyl-4-yl)methyl]-4-chloro-5-bydroxymethyl-2-(ci6-pent-l-en-l-yl)-imidazole (65 mg) wa6 hydrolyzed by a procedure 6imilar to that found in ~xample 85, Part E. Work-up yielded 45 mg of colorle66 601id6; m.p. 148-150.
NMR (200 MHz, DMSO-d6) ~ 7.77 (d, lH): 7.50 (t, lH): 7.38 (t, lH): 7.33 (m, 3H): 7.08 (d, 2H): 6.10 (d, lH): 5.84 (d of t, lH): 5.32 (6, 2H): 4.47 (6, 2H): 2.65 (quart., 2H), 1.45 (6ext., 2H): 0.92 (t, 3H).
Table 19 further illu6trate6 compound6 which were made or could be made by the method6 de6cribed in the 6pecification.
Table 19 R6~ N ~R8 (CH2)r ~3 R13 No. E - R R _ ~P(-C) 267 1 n-butyl Cl CH2OH 4 268 1 n-propyl H CH2OH ~ ~
. O
269 1 n-butyl Cl CH2C02CH3 4-NHC ~
270 1 n-pentyl Cl CH2OH 4 ~
o C(CF3)2 271 1 n-butyl Cl CH2NHCOC3H7 4 O
272 2 n-butyl Cl CH20H
273 1 n-propyl H CH20H 4 -Table 19 (continued) 1 3 3 4 0 ~ 2 No. r _ R R R HP('C) 274 1 n-butyl CF3 CH20H 4b NHP-OH
275 1 n-butyl Cl CH20H 4 ~ H
276 1 n-butyl H CH20H ~
276 1 n-hexyl Cl CH2NHC2CH3 4~
OH O
CH-P-OH
278 1 n-butyl ClCH20H 4 279 1 n-butyl ClCH20H 4 N~,NH
280 0 n-butyl ClCH20H
281 1 n-propyl Cl CH20H 4 Table 19 (continue~) 1 3 3 4 0 9 2 _x r R R R R ~P(C) 282 1 n-butyl Cl CH20H 4 ~
C~CO--NHOCH
283 1 n-butyl Cl CH20H 4 ~
284 1 n-hexyl H CH20H 4~C~
Cl ~, 285 1 n-butyl Cl CH20H 4 N=N
N ~ NH
286 1 n-propyl H CH20H
U NH
N=N
N--N~
287 1 n-butyl Cl (CH2)2F 4~
C~
288 1 n-butyl Cl CH20CNHCH3 4-274 1 3340~2 Table 19 (continued) No. r R R _ R Mr( 289 ~ n-butyl Cl CH20CNHCH3 4 ~
C~
290 1 n-propyl H CH2NHCOCH2CH2CH3 4 4 ~ 3 291 1 n-pentyl H CH2NHCNHCH3 ~
292 1 n-butyl ( 2)3 ~ 181-182.5 293 1 n-butyl C1 CH20N02 293 1 n-butyl Cl CH2~ ~ 4 295 1 n-butyl Cl CH20H 4-~(CH3)C0 296 1 n-butyl Cl CH20H 4-CH20 ~
297 1 n-buLyl Cl CH20H 4-SCH
-Table 19 (continucd) 1 3 3 4 0 ~ 2 No. r R R R R MP(C) 298 1 n-butyl Cl CH20H 4-SCH2~3 299 1 n-butyl Cl CH20H 4-COI;H
300 1 n-butyl Cl CH20H 4-NHCH
lS 301 1 n-butyl Cl CH20H 4-N~C ~ 3 20 302 1 n-propyl Cl CH20H 4-S02NH2b 303 1 n-pentyl Cl CH20H 4-CH2NH~3 304 1 n-hexyl Cl CH20H 4-CF=CF ~ ) 305 1 n-butyl Cl CH20H 4-CH=CFb 306 1 n-butyl H CH20H 4- CH2CH
~ 276 Table 19 (continued) l 3 3 4 0 9 2 Ex.
No. r R6 R7 R8 Rl3 MP(C) ~ 2CF3 307 1 n-butyl Cl CH20H 4- ~
308 1 n-butyl Cl CH20H OH
309 1 n-butyl Cl CH20H 4-CH-~
310 1 n-butyl Cl CH20H INOCH3 311 1 n-butyl Cl CH20H 4-C ~
CF3SO2'N
H
312 1 n-propyl H CH20H 4-C ----- ~
313 1 n-pentyl Cl CH20H O /O
314 1 n-butyl Cl CH=CHCH20H 4 ~ 103-104.5 ~, Utility 277 I 3340~2 The hormone angiotensin II (AII) produce6 numerous biological responses (e.g. va60con~triction) through stimulation of its receptor6 on cell membranes.
For the purpo~e of identifying compound6 6uch a6 AII
antagoni~t6 which are capable of interacting with the AII receptor, a ligand-receptor binding a66ay wa6 utilized for the initial ~creen. T~e a66ay wa6 carried out according to the method de6cribed by tGl066mann et al., J. Biol. Chem., 249, 825 (1974)], but with 60me modifications. The reaction ~ixture contained rat adrenal cortical micro60me6 (60urce of AII receptor) in Tri6 buffer and 2 nM of H-AII with or without potential AII antagoni~t. T~is mixture wa6 incubated for 1 hour at room temperature and the reaction wa6 6ub6equently terminated by rapid filtration and rin6ing through gla66 micro-fibre filter. Receptor-bound 3H-AII trapped in filter wa6 quantitated by 6cintillation counting. The inhibitory concentration (IC50) of potential AII antagoni6t which give6 50%
di6placement of the total 6pecifically bound H-AII
i6 pre6ented a6 a mea6ure of the affinity of 6uch compound for the AII receptor (6ee Table 20).
The potential antihyperten6ive effect6 of the compounds of this invention may be demonstrated by admini6tering the compounds to awake rat6 made hyperten6ive by ligation of the left renal artery ~Cangiano et al., J. Pharmacol. Exp. Ther., 208, 310 (1979)~. Thi6 procedure increa6e6 blood pre66ure by increasing renin production with consequent elevation of AII level6. Compounds are admini6tered orally at 100 mg~kg a~d~or intca~enou61y via a cannula in the jugular vein at 10 mg/kg. Arterial blood pre66ure is continuously mea6ured directly through a carotid artery cannula and recorded using a pres6ure -278 1 3340~2 transducer and a polygraph. Blood pres6ure level6 after treatment are compared to pretreatment level6 to determine the antihyperten6ive effect6 of t~e compounds (See Table 20).
Table 20 Angioten6in II Antihyperten6ive Receptor Effect6 in Renal Bindinq HYperten6ive Rat6 IC50 Intravenou6 Oral Ex. No. (~molar) ActivitYl Activity2 1 1.80 + NA
2 (60dium ~alt) 0.140 + NA
3 (60dium 6alt) 0.420 NA
4 (60dium 6alt) 0.280 + NA
5 (60dium 6alt) 0.190 NA
6 5.70 NT
7 0.420 + NA
8 (60dium 6alt) 0.790 NA
9 (60dium 6alt) 5.80 NT
10 (60dium 6alt) 0.190 NT
11 (60dium 6alt) 0.380 NA NA
12 (60dium 6alt) 0.030 + NA
5.25 (t, lH, 5Hz: absent in D20 shake): 4.15 (d, 2H, 5Hz: s in D20 6hake). Mas6 Spec. 265.
PART B: Preparation of 5-Hydroxymethyl-2-methylthio-1-(4-nitrobenzyl~imidazole An ethanolic solution of sodium ethoxide was prepared by the gradual addition of 60dium hydride (0.70 g of 60~ NaH in mineral oil, 17.6 mmol) to absolute ethanol (150 mL). To thi6 5-hydroxymethyl-25 2-mercapto-1-(4-nitrobenzyl)imidazole (3.9 g, 14.7 mmol) wa~ added and after being stirred 5-10 minutes, iodomethane (2.5 g, 1.1 mL, 17.6 mmol) was added.
After being stirred 3 hours at room temperature, the mixture was concentrated on a rotary evaporator and the residue was partitioned between ethyl acetate (500 mL) and water (250 mL). The aqueous phase wa6 further extracted with ethyl acetate (250 mL) and the combined organic phases were washed with water (150 mL), saturated aqueous sodium chloride (150 mL), dried (MgS04), filtered and concentrated to leave 4.1 g of 133 ~ 3340q 2 yellow-brown 601id. Recry~tallization from ethyl acetate gave 2.6 g (64%) of light yellow-broWn powder;
m.p. 160-162. NMR (200 MHz, DNSO-d6) ~ 8.20 (d, 2H, 7Hz); 7.30 (d, 2H, 7Hz); 6.95 (6, lH); 5.40 (6, 2H); 5.20 (t, lH, 5Hz; absent in D2O 6ha~e): 4.40 (d, 3H, 5Hz; 6 in D20 6hake); 3.40 (6, 2H;
monohydrate: ~ 3.5 in D20): 2.45 (6, 3H).
Mas6 Spec. 279.
0 PART C: Preparation of 1-(4-Aminobenzyl)-5-hydroxy-methyl-2-tmethYlthio)imidazole Thi6 compound was prepared according to the procedure described in Example 54, Part E, from 5-hydroxymethyl-2-methylthio-1-(4-nitrobenzyl)imid-azole (21 g, 75.2 mmol) and iron powder (75 g, 1.3mol) there was obtained 13.5 g (72%) of a yellow hygroscopic 601id. NMR (200 MHz, CDC13) ~ 6.90 (6, lH); 6.85-6.45 (g, 4H, SHz,51Hz): 5.10 (6, 2H);
4.40 (6, 2H): 2.40 (6, 3H). Mas6 Spec. 249.
PART D: Preparation of 1-[4-(2-Carboxybenzamido)-benzyl]-5-hydroxymethyl-2-(methylthio)-imidazole This compound was prepared according to the procedure de6cribed in Example 55, Part F, though in this case the reaction was run in chloroform and the filtered product wa6 washed with chloroform and ether.
From 1-(4-aminobenzyl)-5-hydroxymethyl-2-(methylthio)-imidazole (323 mg, 1.3 mmol) and phthalic anhydride (192 mg, 1.3 mmol) there wa6 obtained 488 mg (95%) of the title compound a6 a yellow powder: m.p. 115-118 (dec.). NMR (200 MHz, CDC13/DMSO-d6) ~ 9.80 (6, lH): 8.00-6.85 (m, 9H): 5.20 (6, 2H): 4.40 (6, 2H);
2.50 (s, 3H). Mass Spec. 379 (M-H2O).
Example 73 Preparation of l-t4-(2-Carboxybenzamido)benzyl-5-hydroxymethyl-2-methoxYimidazole By repeating Example 72, Part6 C and D, but 6ubstituting 5-hydroxymethyl-2-methoxy-1-(4-nitro-benzyl)imidazole a6 6tarting ~aterial in Part C, the compound l-t4-(2-carboxybenzamido)benzyll-5-hydroxy-methyl-2-methoxyimidazole can be prepared.
ExamPle 74 PART A: Preparation of tran6-2-(Trifluoromethane-6ulfonamido)cYclohexanecarbo~ylic acid Ethyl trans-2-(trifluoromethane6ulfonamido)cyclo-hexanecarboxylate wa6 ~ynthe~ized from ethyl tran6-2-aminocyclohexanecarboxylate lE. J. Moriconi and P. H.Mazzocchi, J. Orq. Chem., 31, 1372 (1966)] by the procedure de6cribed in Example 21. The crude product (2.59 g, 8.55 mmol, 1 eq) wa~ then hydrolyzed by refluxing in 1.00N NaOH (26.5 mL, 26.5 mmol, 3.1 eq) overnight under N2. Water (100 mL) wa6 then added and the pH adjusted to 3 u6ing 1_ HCl. The aqueous wa6 extracted with ethyl acetate (3 x 100 mL), the organic layer6 dried (MgS04) and concentrated to yield a cry6talline white 601id which wa~ recry6tal-lized from n-butyl chloride. Obtained 1.71 g of product: m.p. 114.5~ .5. NMR (200 MHz, DMSO-d6) 12.47 (bs, lH): 9.52 (bs, lH): 2.35 (d of d of d, lH, J= 10,10,4Hz): 2.10-1.13 (m, 9H). Anal. Calcd.
for C8H12~3NO4S: C, 34.91: H, 4.39: N, 5.09.
Pound, C, 34.73: H, 4.22; N, 5.04.
- 1 3340~2 PART B: Preparation of Methyl 2-butyl-4-chloro-1-t4-(trans-2-(trifluoromethane6ulfonamido)cyclo-hexanecarboxamido)benzyl]imidazole-5-acetate and methyl 2-butyl-4-chloro-1-t4-(cis-2-(tri-fluoromethane6ulfonamido)cyclohexanecarbox-amido)benzyl~imidazole-5-acetate trans-2-(Trifluoromethanesulfonamido~cyclohexane-carboxylic acid (500 mg, 1.82 mmol, 1 eq) and thionyl chloride (2.30 mL, 31.5 mmol, 17.3 eq) were mixed and refluxed for 2 hours. The exces6 thionyl chloride wa~
removed in vacuo and the residue suspended in toluene.
The toluene wa6 removed by rotary evaporation and the procedure repeated to remove trace6 of thionyl chlor-ide. Final rotary evaporation yielded 460 mg of white cry6talline acid chloride product which wa6 u6ed with-out furtber purification (IR 1789 cm 1).
Methyl 2-butyl-4-chloro-1-(4-aminobenzyl)-imidazole-5-acetate (530 mg, 1.57 mmol, 1 eq), tran6-2-(trifluoromethanesulfonamido)cyclohexanoyl chloride (460 mg, 1.57 mmol, 1 eq) and 60dium bicarbonate (400 mg, 4.70 mmol, 3 eq) were mixed and 6tirred in chloro-form (20 mL) overnight. Water (100 mL) wa6 then added, and the pH adjusted to 4 with lN HCl. The aqueou~ was extracted with methylene chloride (3 x 100 mL) and the organic layer6 dried and concentrated. Gradient flash chromatography of the residue in 60:40 hexane/ethyl acetate to 100% ethyl acetate over 6ilica gel yielded two isomer6: both of which were i601ated a~ gla66e~.
The faster eluting product being the minor Ci8 i60mer (170 mg) while the 610wer being the major trans isomer (520 mg).
_ 136 1 ~340~2 trans-Isomer; NMR (200 MHz, CDC13) ~ 8.18 (s, lH): 7.42 (d, 2H, J= lOHz); 6.84 (d, 2H, J= lOHz);
6.47 (bd, lH, J= 8Hz): 5.07 (s, 2H); 3.72 (m, lH):
3.57 (s, 3H); 3.47 (s, 2H); 2.53 (t, 2H, 7Hz):
2.24-1.12 (m, 13Hz): 0.82 (t, 3H, J= 7Hz). Anal.
Calcd. for C25H32C1~3N4O5S: C, 50.63 H, 5.q4 N, 9.45. Found: C, 50.64: H, 5.44: N, 9.16. Mass Calcd. for C25H32ClF3N4O5S: 592.173q. Pound:
592.1731.
cis-Isomer: NMR (200 MHz, CDC13) ~ 7.94 (s, lH): 7.42 (d, 2H, J= lOHz): 6.88 (d, 2H, J= lOHz):
6.52 (bd, 2H, J= 8Hz): 5.11 (s, 2H): 3.75 (m, lH):
3.63 (8, 3H): 3.48 (s, 2H): 2.56 (t, 2H, 7Hz):
2.29-1.25 (m, 13H): 0.86 (t, 3H, J~ 7Hz). Anal.
25 32 3 4 5S: C, 50.63: H, 5.44.
Found: C, 49.87: H, 5.65. Mass Calcd. for C25H32ClF3N4O5S: 592.1734. ~ound: 592.1689.
ExamPle 75 PART A: PreParation of 2-Butyl-4,5-dicyanoimidazole Ethyl pentanimidate hydrochloride (42.66 g, 257.8 mmol, 1 eq), diaminomaleonitrile (27.90 g, 258.1 mmol, 1 eq) and pyridine (400 mL) were mixed and refluxed for 48 hours under N2. The solvent was removed by rotary evaporation.
The residue wa6 taken up in ethyl acetate and filtered through a pad (3" Y 4") of ~lorisil*. The solvent was removed in vacuo and the residue fla6h chromatographed in 60:40 ~exane/ethyl acetate over silica gel to give 16.59 g of a yellow solid w~ich was used in the following step without further purifica-tion. An analytical sample was prepared by recrystal-li~ing the crude product (3.03 g) from ether/~exane to give 1.55 g of yellow crystals; m.p. 108.0-109Ø
* trade mark .~ .
-NMR (200 MHz, CDC13) ~ 2.86 (t, 2H, J= 7Hz): 1.77 (t of t, 2H, J= 7,7Hz); 1.41 (t of q, 2H, J= 7,7Hz):
0.98 (t, 3H, J= 7Hz). Anal. Calcd. for CgHloN4:
C, 62.05; H, 5.79: N, 32.16. Pound: c, 62.28: H, 5.81; N, 32.22. Mass ~pectrum ~hows M-H pea~. Ma~s Calcd. for CgHloN4-H: 173.0827. ~ound: 173.0785.
PART B: Preparation of 2-Butyl-4,5-dicyano-1-(4-nitrobenzYl)imidazole 2-n-Butyl-4,5-dicyano-1-(4-nitrobenzyl)imidazole was prepared from 2-n-butyl-4,5-dicyanoimidazole by the procedure in Example 1, Part A u6ing q-nitrobenzyl bromide as the alkylating agent. The product wa6 obtained as an oil. NMR ~200 MHz, CDC13) ~ 8.29 (d, 2H, J= lOHz): 7.29 (d, 2H, J. lOHz): 5.36 (6, 2H);
2.67 (t, 2H, Jz 7Hz): 1.70 (t of t, 2H, J. 7,7Hz):
1.36 (t of q, 2H, J= 7,7Hz); 0.86 (t, 3H, J= 7Hz).
~ass Calcd. for C16H15N502 309.1211.
PART C: Preparation of 1-(4-Aminobenzyl)-2-butyl-4,5-dicyanoimidazole A mixture of 2-butyl-4,5-dicyano-1-(4-nitrobenz-yl)imidazole (2.00 g, 6.5 mmol, 1 eq), tin dichloride dihydrate (7.30 g, 32.3 mmol, 5 eq) and ethanol (13 mL) wa~ 6tirred and heated at 70 for 50 minute~. The reaction wa6 terminated by pouring the mixture onto ice and adjusting the pH to 8 with 6aturated aqueous NaHCO3. The aqueou6 mixture wa6 extracted with ethyl acetate (3 x 100 mL) and the organic layer~ were dried (MgS04) and concentrated to give a thic~ amber oil, Thi6 oil was flash chromatographed over 6ilica qel in 75:25 to 70:30 hexane/ethyl acetate yielding 330 mg of yellow crystals; m.p. 99.0-103.5. NMR (200 MHz, CDC13) ~ 6.97 (d, 2H, J= lOHz); 6.68 (d, 2H, J=
lOHz); 5.10 (s, 2H); 2.69 (t, 2H, J= 7Hz); 1.72 (t of t, 2H, J= 7,7Hz); 1.38 ( t of q, 2H, J= 7,7Hz); 0.91 (t, 3H, J= 7Hz). Mas6 Calcd. for C16H17N5:
279.1483. Found: 279.1489.
PART D: Preparation of 2-Butyl-4,5-dicyano-1-14-((N-trifluoromethane6ulfonyl)anthranilamido)-benzyl~imidazole The title compound was prepared by the procedure described in Example 30 starting with 1-(4-aminobenz-yl)-2-butyl-4,5-dicyanoimidazole and N-(trifluoro-methanesulfonyl)anthranilic acid chloride. NMR (200 MHz, CDC13 ~ DMS0-d6) ~ 7.98 (d, lH, J= 7Hz): 7.32 (d, 2H, J= 7Hz): 7.62 (d, lH, J= 7Hz); 7.47 (d of d, lH, J= 7,7Hz): 7.24 (d of d, lH, Js 7,7Hz): 7.15 (d, 2, J=
7,7Hz): 5.32 (6, 2H): 2.75 (t, 2H, J= 7Hz): 1.70 (t of t, 2H, J= 7,7Hz): 1.37 ( t of g, 2H, J= 7,7Hz): 0.92 (t, 3H, J= 7Hz). ~ass Calcd. for C24H21F3N603S:
503.1348. Found: 530.1343.
ExamPle 76 PART A: ~reparation of Metbyl l-t4-(N-benzylamino)-benzYl~-2-butYl-4-chloroimidazole-5-acetate A mixture of methyl 1-(4-aminobenzyl)-2-butyl-4-chloroimidazole-5-acetate (1.00 g, 3.0 mmol, 1 eg), benzaldehyde (0.30 mL, 3.0 mmol, 1 eq), 4A powdered molecular 6ieves (enough to make a slurry) and 40 mL
THP was 6tirred overnight. The next day, more benz-aldehyde (0.2 mL) and acidic A1203 (activity 1, lg) were added and t~e 61urry stirred anotber 24 ~ours.
The solids were filtered and the solvent from the filtrate removed in vacuo. The re6idue was dis~olved in methanol (10 mL) and sodium cyanoborohydride was added (0.19 9, 3.0 mmol, 1 eq). The mixture was stirred for 24 hours, after which the 601vent was removed in vacuo to yield a green oil which was flash chromatographed over silica gel in 70:30 hexane/ethyl acetate to give 740 mg of product as an oil. NMR (200 MHz, CDC13) ~ 7.42 - 7.24 (m, 5~): 6.74 td, 2H, J=
7Hz): 6.56 (d, 2H, J= 7Hz): 4.98 (s, 2H): 4.31 (6, 2H): 3.61 (s, 3H): 3.48 ts. 2H) 2.60 (t, 2H, J= 7Hz):
1.67 (t of t, 2~, J= 7,7Hz): 1.35 (t of g, 2H, Js 7,7Hz): 0.89 (t, 3H, Js 7Hz). Ma66 Calcd. for C24H28C1~302: 425.1868. Found: 425.1853.
PART B: Preparation of Methyl 2-butyl-1-t4-(N-benzyl-N-(2-(trifluoromethanesulfonamido)benzoyl)-amino)benzYll-4-chloroimidazole-5-acetate The title compound was prepared from the compound of Part A by the procedure described in Example 30.
NMR (200 MHz, CDC13) ~ 7.59 (d, lH, Js lOHz):
7.33-7.16 (m, 6H): 6.89 (d, 2H, Js lOHz): 6.76 (d, 2H, J= lOHz); 6.93-6.70 (m, 2H): 5.12 (6, 2H); 5.02 (6, 2H); 3.55 (s, 3H); 3.39 (6, 2H); 2.47 (t, 2H, J= 7Hz);
1.64 (t of t, 2H, J= 7,7Hz); 1.30 (t of q, 2H, J=
7,7Hz); 0.88 (t, 3H, J= 7~z). Anal. Calcd. for C32H32ClF3N405S: C, 56.76; H, 4.76; N, 8.27.
Found: C, 56.64; H, 4.90; N, 7.98.
Example 77 PART A: Preparation of 2-n-Butyl-4-chloro-5-methoxy-methY~ lN-methYl-4-aminobenzyl~imidazole 1-(4-Aminobenzyl)-2-n-butyl-4-chloro-5-(methoxy-methyl)imidazole (10.94 g) and ethyl formate (150 mL) were mixed and refluxed overnight. The exces6 ethyl formate was removed in vacuo and another 150 mL added and the mixture was refluxed overnight again. The excess ethyl formate was removed in vacuo and the residue flash chromatographed over silica gel in 1:1 hexane/ethyl acetate to yield 9.52 g of a golden oil which 610wly cry~tallized after 6everal days. Thi6 oil (9.40 g, 28 mmol, 1 eq) was dis601ved in TH~ and to it LAH (lM in THF, 84.0 mL, 84 mmol, 3 eq) was slowly added via syringe under N2. After 6tirring for 1 h, the mixture was worked up a~ described in Pie6er and Fieser, V.l pg. 584 (Steinhardt procedure) to yield 8.47 g of an orange oil. NMR (200 MHz, CDC13) ~ 6.84 (d, 2H, J= lOHz); 6.55 (d, 2H, J.
lOHz); 5.02 (6, 2H): 4.26 (s, 2H); 3.27 (8, 3H); 2.81 (s, 3H); 2.58 (t, 2H, J= 7Hz); 1.67 (t of t, 2H, J=
7,7Hz); 1.35 (t of q, 2H, J~ 7,7Hz); 0.87 (t, 3H, J=7Hz). Anal. Calcd. for C17H24ClN30: C, 63.44;
H, 7.52; N, 13.06. Found: C, 63.60; H, 7.61; N, 12.86.
PART B: Preparation of 2-n-Butyl-4-chloro-5-methoxy-methyl-l-t4-(N-methyl-2-carboxy-3,6-dichloro-benzamid)benzyllimidazole 2-n-Butyl-4-chloro-5-methoxymethyl-1-tN-metbyl-4-aminobenzyl~imidazole (2.00 g, 6.2 mmol, 1 eq) and 3,6-dichlorophthalic anhydride (1.35 g, 6.2 mmol, 1 eq) were reacted by the procedure described in Example 2, Part D to give 2.37 g of a white powder; m.p. 120.0-123.5. The NMR 6hows a 7:2 mixture of conformers in DMS0-d6. NMR (200 MHz, DMS0-d6) ~ (major conformer only) 14.25 (m, lH): 7.76-6.85 (m, 6H); 5.09 (s, 2H); 4.18 (s, 2H); 3.06 (s, 3H); 2.37 (t, 2H, J=
7Hz); 1.38 (t of t, 2H, J= 7,7Hz); 1.21 (t of q, 2H, J= 7,7Hz); 0.77 (t, 3H, J= 7Hz). Anal. Calcd. for C25H26C13N304: C, 55.72; H, 4.86; Cl, 19.74, ~ound: C, 55.48; H, 4.88; Cl, 19.77.
Example 78 PART A: Preparation of 2-n-Butyl-1-(4-carbomethoxy-benzyl)-4-chloro-5-(methoxymethYl)imidazole) 2-Butyl-4-chloro-S-hydroxymethyl-1-(4-carboxy-benzyl)imidazole (17.6 g), methanol (500 mL) and conc.sulfuric acid (50 mL) were mixed and refluxed overnight. Pota6sium carbonate (100 g) was then carefully added to the 601ution which was cooled over ice. The reaction mixture wa6 then stirred for 2.5 hours. The solvent was removed in vacuo and the residue di6~01Yed in water (1 L). Thi6 aqueous mixture wa6 extracted with ethyl acetate (3 s 400 mL). The organic layer~ were combined, dried (NgS04) and t~e 601vent removed in vacuo to yield 15.2 g of an oil. NMR (200 MHz, DMSO-d6) ~ 8.46 (d, 2H, J= 9Hz); 7.68 (d, 2H, J= 9Hz): 5.82 (s, 2H);
4.80 (6, 2H): 4.37 (6, 3H); 3.66 (6, 3H); 3.02 (t, 2H, J= 7Hz); 2.01 (t of t, 2H, J= 7,7Hz); 1.77 (t of q, 2H, J= 7,7Hz); 1.33 (t, 3H, J= 7Hz). Anal. Calcd. for C18H23ClN203: C, 61.62; H, 6.61 N, 7.99.
Found: C, 61.79; H, 6.78; N, 7.82.
PART B: Preparation of 2-n-Lutyl-1-(4-carboxybenzyl)-4-chloro-5-(methoxymethYl)imidazole 2-n-Butyl-1-(4-carbomethoxybenzyl)-4-chloro-5-(methoxymethyl)imidazole (15.2 g, 43.3 mmol, 1 eq), 0.5 N KOH in methanol (130 mL, 65.0 mmol, 1.5 eq), water (10 mL) and methanol (50 mL) were mixed and refluxed for 4 hour6. The 601vent wa6 removed in vacuo and the residue di6601ved in water (300 mL).
The pH was adju~ted to 4 with conc. HCl and this aqueous mixture extracted with ethyl acetate (3 x 300 mL). The organic layer~ were combined, dried (MgS04), the solved removed in vacuo and the crude residue recrystallized from hexane/butyl chloride to 1 3~4092 yield 9.6 g of white solid; m.p. 126.5-127.5. NMR
(200 MHz, DMSO-d6) ~ 12.95 (bs, lH); 7.93 (d, 2H, J= 9Hz): 7.16 (d, 2H, J= 9Hz): 5.30 (s, 2H): 4.31 (s, 2H); 3.19 (s, 3H); 2.50 (t, 2H, J= 7Hz); 1.49 (t of t, 2H, J= 7,7Hz); 1.24 (t of q, 2H, J~ 7,7Hz): 0.80 (t, 3H, J= 7Hz). Anal. Calcd. for C17H21ClN203:
C, 60.62; H, 6.29; N, 8.32. ~ound: C, 60.89; H, 6.10; N, 8.03.
0 PART C: Preparation of 2-n-Butyl-l-t4-(N-(2-carboxy-phenyl)carboxamido)benzyl]-4-chloro-5-methoxymethyl~imidazole 2-n-Butyl-1-(4-carboxybenzyl)-4-chloro-5-(methoxymethyl)imidazole (6.00 g, 17.8 ~mol, 1 eq), thionyl chloride (13.0 mL, 178 ~mol, 10 eq) and chloroform (100 mL) were mixed and refluxed for 6 h.
The solvent wa~ removed in vacuo, and the re~-idue dis601ved in toluene. The solvent was removed on the rotary evaporator and the evaporation from toluene repeated to remove all of the thionyl chloride. This yielded 6.0 g of acid chloride a~ an amber gum. lR
1776, 1745 cm . Anthranilic acid (0.737 g, 5.36 mmol, 1 eq) was di~solved in 1.000 N NaOH (10.75 mL, 10.7 mmol, 2 eq) and water (100 mL) and cooled over ice. The aforementioned acid chloride (1.91 g, 5.36 mmol, 1 eq) dissolved in THF (50 mL) was ~lowly added via a dropping funnel to the 6tirred and cooled antbranilic acid solution. The following day, more anthranilic acid (74 mg, 0.536 mmol, 0.1 eq) wa~ added to bring the reaction to completion. After 1.5 h, the ~olution was acidified to pH=5 with lN HCl and extracted with ethyl acetate (1 x lOOmL). The ethyl acetate layer was then was~ed with water (3 x 50 mL), and brine (1 x 50 mL), dried (MgS04) and the 601vent removed in vacuo to yield 2.28 9 of a brown glass.
-This glass was dissolved in a minimum amount of ethyl acetate and dicyclohexylamine ("DCHA", 1 eq) was added thereto. The salt did not crystallize and therefore was flash chromatographed over silica gel starting in 100~ ethyl acetate and finishing in 1:1 ethyl acetate~-isopropanol to yield 1.44 g of an oil. This oil was dissolved in ethyl acetate (100 mL) and a minimum of methanol, and washed with lN HCl (2x50mL). The ethyl acetate layer was dried (MgS04) and the solvent removed in vacuo to yield 0.52 g of an amber oil. NMR
(200 MHz, CDC13) ~ 12.53 (s, lH): 8.91 (d, lH, J=
8Hz); 8.23 (d, lH, J= 7Hz): 8.08 (d, 3H, J= 7Hz): 7.62 (t, lH, J= 6Hz): 7.11 (t, 2H, J= 7Hz): 5.30 (6, 2H):
4.30 (s, 2H): 3.30 (s, 3H); 2.72 (t, 2H, J= 7Hz): 1.72 (t of t, 2H, J= 7,7Hz): 1.31 (t of q, 2H, J= 7,7Hz):
0.83 (t, 3H, J= 7Hz). Anal. Calcd. for 25 25 3 4 (H20)1.5: C, 59.81: H, 5.85: Cl 7 36 Found: C, 59.78; H, 6.38; Cl, 7.51.
Examples 79-84 in Table 5 were made or could be made by procedures described in Example 78 and by methods familiar to one skilled in the art.
Table S
N ~
a6 ~N~ 8 Ex.
No. R R R R MP(C) 79 n-butyl Cl CH20CH3 N-N~ (,300) -u - ~N,N
H H
-- T~hle 5 (continued) 1 334092 E~ R6 Rl R8 ~ MP (C) 80 n-butyl Cl CH20CH3 _~ (glass)b HO,,J~
81 n-butyl Cl CH2OCH3 ~ (white solid)C
N N~J~
82 n-butyl Cl CH20CH3 H 149-152 ,N~,COOH
.. ~
Lffomer 83 n-butyl Cl CH20CH3t-~ 134.5-136 _ N~l~
COOH
L-isorrler 84 n-butyl Cl CH2OCH3 ~H Cl --N~
HO~,~J
o Cl a NMR (200 MHz, DMSO-d6) ~ 8.01 (d, 2H, J=
7Hz); 7.17 (d, 2H, J= 7Hz); 5.31 (s, 2H);
4.27 (s, 2H); 3.18 (s, 3H); 2.50 (t, 2H, J=
7Hz); 1.50 (t of t, 2H, J= 7,7Hz); 1.21 (t of q, 2H, J= 7,7Hz); 0.~0 (t, 3H, J= 7Hz).
b NMR (200 MHz, CDCl3` ~ 11.52 (s, lH) 8.55 (d, lH, J= 7 Hz)j 8.0 (d, 2H, J= 7Hz) 7.41 (t, lH, J= 7Hz); 7.14 (d, 2H, J= 7Hz); 7.04 (d, lH, J= 7Hz); 5.30 (s, 2H); 4.25 (s, 2H);
3.30 (s, 3H); 2.73 (t, 2H, J= 7Hz); 2.60 (s, 3H); 1.68 (t of t (br), 2H); 1.29 (t of q, 2H, J= 7,7Hz); 0.81 (t, 3H, J= 7Hz).
c NMR (200 MHz, CDCl3) ~ 12.05 (s, lH);
8.88 (d, lH, J= 7Hz); 8.23 (d, 2H, J= 8Hz);
8.11 (d, lH, J= 7Hz); 7.51 (t, lH, J= 7Hz);
7.25-7.11 (m, 3H); 5.29 (s, 2H); 4.31 (s, 2H); 3.29 (s, 3H); 2.62 (t, 2H, J= 7Hz); 1.63 (t of t, 2H, J= 7,7Hz); 1.26 (t of q, 2H
J=7,7Hz); 0.75 (t, 3H, J= 7Hz) IR; 1621,753 cm~l ExamPle 85 1 3 3 4 0 9 ~
PART A: Preparation of Methyl 4'-methylbiphenyl-3-carboxYlate To a stirred solution of 25.2 g of methyl 3-iodobenzoate and 21.0 g of 4-iodotoluene at 180-190 under nitrogen was added 30.3 g of copper powder portionwise over 1 hour. When approximately one-third of the copper had been added, the reaction initiated and the temperature increased spontaneously to 2400. The mixture was allowed to cool to 210, then was held at 210 during the addition of the remaining copper and for an additional hour. The mixture was allowed to cool to room temperature and was filtered employing benzene as solvent; the resulting filtrate was concentrated in vacuum to provide the crude product. Cplumn chromatography on silica gel (elution = 50-100% benzene/hexane) followed by distillation furnished 7.60 g of methyl 4' -methylbiphenyl-3-carboxylate [bp: 114-115C (0.025 torr)] as a colorless oil:
NMR (200 MHz, CDC13): ~ 8.27 (br S, lH): 7.99 (d, lH): 7.77 (d, lH): 7.50 (t, lH): 7.39 (A2B2, 4H): 3.94 (s, 3H): 2.41 (s, 3H).
The following methylbiphenyl starting materials were prepared employing the above procedure.
NMR (200 MHz, CDCl3) C02Me a) A ~ ~ 7.78 (d, lH): 7.46 CH~ (d, lH): 7.35 (t, 2H):
~__J~--J 7.19 (s, 4H): 3.64 (s, 3H): 2.37 (s, 3H) 2 ~ 7.80 (d of d, lH):
~ ~ 7.57 (t of d, lH): 7.41 b)CH~ ~ ~ (m, 2H) 7 19 (s, 4H):
~l `- 1 33409~
Alternatively methyl 4'-methylbiphenyl-2-car-boxylate (compound a) and tert-butyl 4'-methylbiphenyl-2-carboxylate can be prepared by chemistry described by A. Meyers via the following five-step procedure.
Step 1: Preparation of 2-Methoxybenzoyl chloride ~ o 30 g of Z-ani6ic acid in 500 mL of round-bottom flas~ was added dropwise 50 mL of thionyl chloride. After all of the thionyl cbloride was added the reaction mixture was stirred at room temperature for 18 hour6. Excess thionyl chloride was tben distilled off by water aspirator and the remaining liquid was vacuum di6tilled (82~0.7 mm Hg). Desired 2-methoxybenzoyl chloride wa~ obtained a6 a colorless liquid, 32 g.
Step 2: Preparation of 4,4-Dimethyl-2-(2-methoxy-phenyl)oxazoline 20 g of 2-Amino-2-methyl-1-propanol was dissolved in 100 mL of methylene chloride and the mixture wa6 cooled with ice. Meanwhile, 17 g of 2-methoxybenzoyl chloride prepared from Step 1 was placed in a dropping funnel, diluted with 50 mL of methylene chloride and added dropwise. After the addition of the acid chloride, the cooling ice bath was removed and the reaction mixture was stirred at room temperature for 2 hours.
The reaction mixture was concentrated to remove the solvent and the solids obtained were triturated with water, collected by filtration and washed with water. Thus obtained 601ids were dried in vacuo to give a colorless light solid, 20.5 g.
The solid was placed in 200 mL of round-bottom flask and 22 mL of thionyl chloride was added slowly to the solid without any ~olvent. At the beginning of -1 3~4092 the addition the reaction was vigorou6 but wa6 control-lable. After the addition of thionyl chloride wa6 complete, the yellow reaction mixture wa6 6tirred at room temperature for 1 hour. The reaction mixture wa6 poured into 200 mL of ether and the re6ulting 601id6 were collected and wa6hed with ether. The solid6 were di6601ved in 100 mL of water and t~e pH of the 601ution wa6 adju6ted to 10 by adding lN NaOH. The aqueou6 601ution wa6 extracted into ether 3 time6.
The combined ether extracts were dried (Na2S04) and concentrated to give the de6ired product a6 a white 601id, 18 g, m.p. 70-72.
Step 3: Preparation of 2-(4'-Methylbiphenyl-2-yl)-4,4-dimethYloxazoline 4-Methylphenyl Grignard reagent wa6 prepared from 2.5 g of magne~ium and 13 mL of 4-bromotoluene in 200 mL of anhydrou6 THF. The Grignard reagent wa6 added to 10 g of the product from Step 2 in 100 mL of anhydrou6 TH~ and the reaction mixture wa6 6tirred at room temperature for 2 hour6. The reaction mixture wa6 concentrated and the re6idue wa6 treated with 200 mL of 6aturated NH4C1 601ution and the mixture wa6 6tirred at room temperature for 30 minute6. The aqueou6 601ution wa6 then extracted with ethyl acetate. The crude product obtained upon concentration of the ethyl acetate extract6 were purified by fla6h column chromatography (6ilica gel, hexane:ethyl acetate=2:1) to give the de6ired compound a6 a colorle66 liquid, 11.8 g.
Step 4: Preparation of 4'-Methylbiphenyl-2-carboxylic acid A mixture of 10 g of the product from Step 3 and 200 mL of 4.5 N HCl was refluxed for 12 hour6. During this period of time the de6ired compound was isolated as a brownish oil floating on the surface of the reaction medium. The reaction mixture was cooled to room temperature. The product which was oily initially began to solidify upon cooling. The product was extracted with ethyl ether. Upon concentration of the ether extract the de6ired product was obtained a6 a colorless 601id, 7 g, m.p. 140-142.
0 Step 5: Esterification of 4'-methylbiphenyl-2-carboxYlic acid Preparation of methyl 4'-methylbiphenyl-2-carboxylate To 100 mL of methanol was added dropwise 5 mL of acetyl chloride with ice cooling. After ~tirring the mixture for 15 minute6, 5 g of the acid from Step 4 was added at once and the mixture was refluxed for 4 hour6. The reaction mixture was concentrated to remove the ~olvent and the desired methyl e6ter was obtained as a thick liquid, 5 g.
Preparation of tert-butyl 4~-methylbiphenyl-2-carboxylate To a 601ution of 42.4 g of 4'-methylbiphenyl-2-carboxylic acid in 200 mL of methylene chloride at 0was added dropwi6e 20 mL of oxalyl chloride. The reaction wa6 allowed to warm to 25 and then was stirred at 25 for 3 hours. The 601vent was removed in vacuo. The residue wa6 di6601ved in benzene, and the benzene then removed in vacuo to provide 46.1 g of crude acid chloride.
The acid chloride prepared above wa~ di~solved in 600 mL of tetrahydrofuran. To this solution at 0 was added 26.0 g of potassium t-butoxide portionwise -149 1 3~4092 such that the reaction temperature did not exceed 15-20C. The resulting mixture was then allowed to stir at 25C for 1 hour. The reaction mixture was poured into water, and the resulting emulsion was extracte~ with diethyl ether. The combined organic phases were washed with b~ine, dried over anhydrou~
sodium sulfate, filtered, and concentrated.
Distillation provided 49.5 g of tert-butyl 4'-methyl-biphenyl-2-carboxylate (bp 115-120/O.OS torr). NMR
(200 MHz, CDC13): ~ 7.73 (d of d, lH), 7.46-7.27 (m, 3H); 7.18 (s, 4H): 2.40 (s, 3H): 1.30 (s, 9H).
PART B: Preparation of Methyl 4'-bromomethylbiphenyl-3-carboxylate A solution of 7.31 g of Methyl 4'-methylbiphenyl-3-carboxylate, 5.75 g of N-bromosuccinimide, 0.125 g of azo(bisisobutyronitrile), and S00 mL of carbon tetrachloride was refluxed for 3 hours. After cooling to room temperature the resulting suspension was filtered and then concentrated in vacuo to provide 9.90 g of crude methyl 4l-bromomethylbiphenyl-3-carboxylate which was used in a subsequent reaction without further purification; ~MR (200 MHz, CDC13):
~ 8.28 (s, lH); 8.05 (d, lH); 7.79 (d, lH);
7.67-7.48 (m, SH); 4.55 (s, 2H); 3.98 (s, 3H).
The following bromomethylbiphenyl intermediates were prepared employing the above procedure.
CD~ NMR (200 MHz, CDC13) a) Er ~ ~ 7.82 (d, lH);
7.59-7.23 (m, 7H); 4.52 (s, 2H); 3.62 (s, 3H) 150 1 3340~2 b) y ~ 7.86 (d of d, lH):
~ 7.62 (t of d, lH);
2r 7.53-7.21 (m, 6H); 4.52 (s, 2H) C02C ( CH3 ) 3 c) ~ ~ ~ 7.79 (d, lH);
7.56-7.24 (m, 7H); 4.51 ~r (s, 2H); 1.25 (s, 9H).
PART C: Preparation of l-t(3'-Carbomethoxybiphenyl-4-yl)methyl]-2-butyl-4-chloro-5-hydroxymethyl-imidazole To a suspension of 1.43 g of sodium methoxide in 20 mL of dimethylformamide at 25 was added a 601ution of 5.00 g of 2-butyl-4(5)-chloro-5(4)-hydroxymethyl imidazole in 15 mL of DMF. The resulting mixture was stirred at 25 for 0.25 hours, and then to this mix-ture was added dropwise a solution of 9.90 g of methyl g'-bromomethylbiphenyl-3-carboxylate in 15 mL of DMF.
Finally, the reaction mixture was stirred at 40 for 4 hours. After cooling to 25, the solvent was removed in vacuo. The residue was dissolved in ethyl acetate, and this solution was washed with water and brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product contains two regioisomers, the faster moving one by TLC being the more potent isomer. Column chromatography on silica gel (elution:10-25% ethyl acetate/benzene) afforded 3-85 g of l-t(3~-carbomethoxybiphenyl-4-yl)meth 2-butyl-4-chloro-5-hydroxymethylimidazole (m.p.
162-163), the regioisomer of higher Rf; NMR (200 MHz, CDC13) 8.24 (s, lH): 8.03 (d, lH); 7.76 (d, lH); 7.52 (t, lH); 7.33 (A2B2, 4H); 5.27 (6, 2H);
4.52 (d, 2H); 3.93 (s, 3H); 2.60 (t. 2H); 1.89 (t, lH); 1.67 (quint., 2H); 1.35 (sext., 2H); 0.88 (t, 3H).
151 t 3340~2 PART D: PreparatiOn of l-t(3'-Carbomethoxybiphenyl-4-yl)methYll-2-butyl-5-hydroxymethylimidazole A mixture of 1.00 g of 10S palladium/carbon and 1.00 g of 1-[(3'-carbomethoxybiphenyl-4-yl)methyl~-2-butyl-4-chloro-5-hydroxymethyl imidazole in 20 mL of methanol wa6 6tirred at 25 for five minute6. Hydrogen gas was bubbled into the solution, and the mixture wa6 6tirred under H2(g) (1 atm.) at 25 for 3.5 hour6.
The mixture wa6 filtered, and the re6ulting 601utioD
concentrated in vacuo. Column chromatography (elution:
0-5% methanol/chloroform) furnished 0.33 g of 1-1(3'-carbomethoxybiphenyl-4-yl)methyll-2-butyl-S-hydroxy-methyl imidazole. NMR (200 MHz, DMSO-d6) ~ 8.20 (8, lH): 7.98 (d, 2H): 7.65 (t, 18): 7.41 (A2M2, 4H): 6.80 (6, lH): 5.30 (6, 2H): 5.12 (t, lH): q.37 (d, 2H); 3.90 (6, 3H): 2.52 (t, 2H): 1.51 (quint., 2H): 1.27 (sext., 2H): 0.80 (t, 3H).
The following intermediate6 6hown below were al60 prepared by the procedures described in Part C or Part~ C and D above.
.
~6 ~ N ~ R
?R1 3 ~ ~13 R R R MP(C) n-butyl Cl CH20H4 ~ 162-163 n-butyl Cl CH20H3 ~ (oil)a C\02Me n-butyl H CH20H4 ~ 139-141 C02tBu n-butyl I CH20~4. ~ 125-126 n-butyl CH20H Cl 4 ~ 116-118 C0 Me n-butyl C~l20H Clq ~ lZ2-124 C02tBu a NMR (200 MHz, CDC13) ~ 7.82 (d of d, lH);
7.58 (t of d, lH); 7.44 (t of d, lH); 7.35 (d of d, lH); 7.11 (AzBz, 4H); 5.21 (6, 2H);
4.46 (s, 2H); 2.59 (t, 2H); 1.60 (quint, 2H);
1.29 (sext., 2H); 0.82 (t, 3H).
PART E: Preparation of l-t(3'-Carboxybiphenyl-4-yl)-methyl]-2-butyl-4-chloro-5-hydroxymethyl-imidazole A 601ution of 0.30 g of 1-~(3'-carbomethoxy-biphenyl-4-yl)methyl]-2-butyl-4-chloro-5-hydroxymethyl-imidazole in 16 mL of ethanol and 8 mL of 10~ aqueous sodium hydroxide wa6 refluxed for 5 hour6. After cooling, the reaction mixture was filtered, and the ~olvent was removed in vacuo. The re6idue was di6-solved in water, and the solution wa6 acidified to pH
3.5 u6ing hydrochloric acid. The precipitated 601id wa6 recovered by filtration and recry~tallized from aqueous ethanol to furnish 0.24 g of 1-[(3'-carboxy-biphenyl-4-yl)methyl]-2-butyl-4-chloro-5-hydroxymethyl-imidazole (m.p. 180-181): MMR (200 MHz, DMSO-d6):
8.26 (s, lH); 8.04 (d, lH): 7.77 (d, lH): 7.52 (t, lH); 7.36 tA2M2, 4H); 5.30 (6, 2H); 4.48 (~, 2H);
2.57 (t, 2H); 1.64 (quint., 2H); 1.34 (6ext., 2H);
0.87 (t, 3H).
Example 86 PART A: Preparation of 1-[(3'-Carbomethoxybiphenyl-4-yl)methyl]-2-butyl-4-chloro-5-methoxymethyl-imidazole A fiolution of 5.00 g of 1-[(3'-carbomethoxybi-phenyl-4-yl)methyl]-2-butyl-4-chloro-5-hydroxymethyl-imidazole and 1.0 mL of conc. 6ulfuric acid in 200 mL
of met~anol was refluxed for 20 hours. After cooling, -the solvent was removed in vacuo, and the residue was poured into saturated sodium bicarbonate solution.
The resulting mixture was extracted with methylene chloride, and the combined organic phases were washed 5 with water and brine, dried over anhydrou6 sodium sulfate, filtered, and concentrated in vacuo. Column chromatography on silica gel (elution: 0-20~ ethyl acetate~benzene) furnished 5.35 g of 1-t(3'-carbo-methoxybiphenyl-4-yl)methyl~-2-butyl-4-chloro-5-methoxymethylimidazole: NNR (200 MHz, CDC13):
8.26 (t, lH): 8.03 (d of t, lH); 7.76 (d of t, lH):
7.51 (t, lH): 7.33 (A2M2, 4H); 5.20 (6, 2H); 4.31 (s, 2H); 3.94 (6, 3H): 3.27 (s, 3H): 2.59 (t, 2H);
1.68 (quint., 2H); 1.34 (sext., 2H); 0.87 (t, 3H).
The following intermediates were prepared or could be prepared using the above described procedure.
R6lN~R8 1 3 3 4 0 9 2 ~3 --QR 13 ~ R
R R _ MP(C) C ~ H3 n-butyl Cl CH20CH3q~ Oila N~
- n-butyl Cl CH20CH34~,3 oilb C ~ H3 n-butyl Cl CH20~ 34~ Oilc a -NMR (200 MHz, CDC13) ~ 7.82 (d, lH, J= 7Hz);
7.50 (t, lH, J= 7Hz); 7.38 (t, lH, J= 7Hz):
7.30 (d, lH, J= 7Hz): 7.26 (d, 2H, J= lOHz):
7.00 (d, 2H, J= lOHz): 5.14 (s, 2H): 4.32 (s, 2H): 3.63 (s, 3H): 3.28 (s, 3H): 2.60 (t, 2H, J= 7Hz); 1.70 (t of t, 2H, J= 7,7Hz): 1.36 (t of q, 2H, J= 7,7Hz): 0.89 (t, 3H, J= 7Hz).
b -NMR (200 MHz, CDC13) ~ 7.88 (d of d, lH):
7.63 (t of d, lH): 7.51 (t of d, lH) 7.41 (d of d, lH): 7.17 (A282, 4H); 5.20 (s. 2H):
4.30 (s, 2H); 3.27 (s, 3H); 2.59 (t, 2H):
1. 67 (quint ., 2H); 1.35 (sext., 2H); 0.87 (t, 3H).
` -156 1 3340~2 c -NMR (200 MHz, CDC13) ~ 7.84 (d, lH); 7.53 (t, lH), 7.40 (t, lH): 7.29 (m, 3H): 7.04 (d, 2H), 5.22 (6, 2H); 4.36 (s, 2H); 3.65 (8, 3H); 3.61 (sept., lH), 2.59 (t, 2H): 1.68 (quint., 2H): 1.33 (6ext., 2H): 1.14 (d, 6H):
0.88 (t, 3H).
PART B: Preparation of 1-[(3'-Carboxybiphenyl-4-yl)-methyl]-2-butyl-4-chloro-5-methoxymethyl-imidazole By the procedure described in Example B5, Part ~, 3.35 g of the title compound was prepared from 5.35 g of l-t(3'-carbomethoxy)biphenyl-4-yl)methyl]-2-butyl-4-chloro-5-methoxymethylimidazole: NHR (200 MHz, CDC13) ~ 8.33 (s, lH): 8.11 (d, lH): 7.80 (d, lH): 7.55 (t, lH); 7.34 (A2M2, 4H); 5.21 (8, 2H): 4.32 (s, 2H):
3.27 (6, 3H): 2.63 (t, 2H): 1.68 (quint., 2H): 1.34 (sext., 2H): 0.86 (t, 3H).
Example 87 Preparation of l-t(3l-Carboxybiphenyl-4-yl)methyl]-2-butyl-4-chloro-5-acetoxYmethylimidazole A 601ution of 0.10 g of 1-~(3'-carboxybiphenyl-4-yl)methyl]-2-butyl-4-chloro-5-hydroxymethylimidazole, 5 mg of N,N-dimethylaminopyridine, 0.10 mL of acetic anhydride, and 0.14 mL of triethylamine in 8 mL of tetrahydrofuran was 6tirred for 4.5 hour6 at 25. The reaction mixture was poured into water, and dilute aqueous sodium hydroxide was added until the pH of the solution remained in the range of pH 8-9. The solution was then acidified to pH 3.5 using lOS aqueous hydro-chloric acid and extracted with ethyl acetate. The combined organic phases were washed with brine, dried over anhydrous 60dium sulfate and concentrated.
-157 1 }34092 Column chromatography on 6ilica gel (elution: 0.5%
i-propanol/chloroform) furnished 0.065 g of 1-[(3~-carboxybiphenyl-4-yl)methyl]-2-butyl-4-chloro-5-acetoxymethylimidazole, m.p. 172-173; NMR (200 MHz, DMSO-d6): ~ 8.17 (6, lH): 7.93 (t, 2H); 7,61 (t, lH): 7-43 (A2M2, 4H): 5.32 (6, 2H): 4.99 (8, 2H) 2.60 (t, 2H): 1.76 (6, 3H): 1.53 (quint., 2H): 1.28 (sext., 2H): 0.82 (t, 3H).
ExamPle 88 Preparation of 1-[(3'-Trimethylacetoxymethoxycarbonyl-biphenyl-4-yl)methyl]-2-butyl-4-chloro-5-~ydroxymethyl-imidazole To a 601ution of 1.25 g of 1-[(3l-carboxybiphen-yl-4-yl)methyl]-2-butyl-4-chloro-5-hydroxymet~yli~id-azole in 10 mL of dimethylformamide at 25 wa6 added0.17 g of 60dium methoxide followed after 5 minute6 by 0.45 g of chloromethyl trimethylacetate. The mixture was 6tirred at 25 for 4 day6. The 601vent was removed in vacuo and the re6idue wa~ di6sol~ed in ethyl acetate. This 601ution wa~ washed with water and brine, dried over anhydrou6 sodium 6ulfate, filtered and concentrated. Column chromatography on 6ilica gel afforded 1.38 g of the product a6 a glas~y 601id. NMR (200 MHz, CDC13) ~ 7.87 (d, lH); 7.54 (t, lH); 7.43 (t, lH); 7.29 (d, lH); 7.11 (A2B2, 4H); 5.72 (6, 2H); 5.24 (6, 2H); 4.51 (6, 2H); 2.61 (t, 2H); 2.06 (br 6, lH); 1.68 (quint., 2H): 1.36 (6ext., 2H): 1.17 (6, 9H): 0.88 (t, 3H).
ExamPle 89 PART A: Preparation of 4l-methylbip~enyl-2-carboxylic acid Methyl 4'-methylbiphenyl-2-carboxylate (10.0 g, 44.2 mmol, 1 eq), 0.5 N ~OH in methanol (265.5 mL, 133 mmol, 3 eq), and water (50 mL) were mixed and refluxed under N2. After 5 hour~, the solvent was removed ~n vacuo and water (200 mL) and ethyl acetate (200 mL) added. The aqueous layer was acidified with concentrated hydrochloric acid to a pH of 3 and the layers were 6eparated. The aqueous phase wa6 extracted with ethyl acetate (2 x 200 mL), the organic layer6 collected, dried (MgSO4) and the 601vent removed in vacuo to yield 8.71 g of a white solid;
m.p. 140.0-145Ø NMR (200 M~z, D~SO-d6) ~ 7.72 ~d, lH, J= 7Hz): 7.56 (t, lH, J. 7Hz): 7.45 (d, lH, Jz 7Hz): 7.40 (t, lH, J= 7Hz): 7.25 (6, 4H): 2.36 (8, 3H). Anal. Calcd. for C14H12O2: C, 79.23: H, 5.70. Found: C, 79.22; H, S.47.
PART B: PreParation of 4'-MethYl-2-cyanobiphenyl 4~-Methylbiphenyl-2-carboxylic acid (8.71 g, 41 ~mol, 1 eq) and thionyl chloride (30.0 mL, 411 mmol, 10 eq) were mixed and refluxed for 2 hours. The excess thionyl chloride was removed in vacuo and the residue was taken up in toluene. The toluene wa~
removed by rotary evaporation and thi6 toluene evaporation procedure wa~ repeated to ensure that all of the tbionyl chloride wa~ removed. The crude acid chloride wa~ then added slowly to cold (0C) concentrated NH40H (50 mL) so that the temperature was kept below 15. After 15 minute6 of stirring, water (100 mL) was added and solids precipitated.
The~e were collected, washed well with water and dried under high vacuum over P205 in a des6icator overnight to yield 7.45 g of a white 601id; m.p.
126.0-128.5. NMR (200 MHz, DMSO-d6) ~ 7.65-7.14 (m, lOH); 2.32 (~, 3H). Anal. Calcd. for C14H13NO: C, 79.59; H, 6.20; N, 6.63. ~ound C, 79.29; H, 6.09; N, 6.52.
159 1 3340~2 ~ he above product amide (7.45 g, 35 mmol, 1 eq) and thionyl chloride (25.7 mL, 353 mmol, 10 eq) were mixed and refluxed for 3 bour6. The thionyl chloride was removed using the ~ame procedure a~ de6cribed above. The re6idue wa~ wa~hed with a little hexane which partly ~olubilized the product, but removed tbe impurity a~ well to yield 6.64 9 of white ~olid: m.p.
44.0-47Ø NMR (200 MHz, DMSO-d6) ~ 7.95 (d, lH, J= 8Hz): 7.78 (t, lH, Jz 7Hz); 7.69-7.32 (~, 6H): 2.39 (~, 3H). Anal. Calcd. for C14HllN: C, 87.01; H, 5.74. Found: C, 86.44: H, 5.88.
PART C: PreParation of 4~-bromomet~Yl-2-cyanobiphen 4'-methyl-2-cyanobiphenyl (5.59 g) wa~
brominated in the benzylic po6ition by the procedure in Example 85, Part B u6ing benzoyl peroxide a~ an initiator. The product wa~ recrystallized from ether to yield 4.7 g of product; m.p. 114.5-120Ø NMR
(200 MHz, CDC13) ~ 7.82-7.37 (m, 8H); 4.50 (6, 2H). Anal. Calcd. for C14HlOBrN: C, 61.79: H, 3.70; N, 5.15. Found: C, 6Z.15: H, 3.45; N, 4.98.
PART D: Preparation of 2-n-butyl-4-chloro-1-t2~-cyanobiphenyl-4-yl)methyl~-5-(hydroxymethyl)-imidazole 4'-Bromomethyl-2-cyanobiphenyl (4.6 g) wa~
alkylated onto 2-n-butyl-4-chloro-5-(hydroxymethyl)-imidazole by the procedure de~cribed in Example 1, Part A. Work-up and flash chromatography in 1:1 hexane/ethyl acetate over silica gel to ~eparate the regioi~omeric product6 yielded 2.53 g of the fa~ter eluting i~omer. Recry~talli2ation from acetonitrile yielded 1.57 g of analytically pure product: m.p.
153.5-155.5. NMR (200 MHz, CDC13) ~ 7.82-7.43 (m, 6); 7.12 (d, 2, J= 8Hz); 5.32 (5, 2); 4.52 (~, 2);
-2.62 (t, 2, J= 7Hz): 1.70 (t of t, 2, J= 7,7Hz); 1.39 (t of q, 2, J= 7,7Hz): 0.90 (t, 3, J= 7Hz). Anal.
Calcd- for C22H22ClN3 C, 69-56 H~ 5-84 N~
11.06. Found: C, 69.45: H, 5.89; N, 10.79.
PART E: Preparation of 2-n-butyl-4-chloro-5-hydroxy-methyl-l-[(2'-(lH-tetrazol-5-yl)bipbenyl-4-yl)methyllimidazole 2-n-Butyl-4-chloro-1-~(2'-cyanobiphe~yl-4-yl)-methyl]-5-(hydroxymethyl)imidazole (11.93 g) wa6 con~erted to the above product by the procedure de6cribed in Example 90, Part C. The product wa~
purified by fla6h chromatography in 100% ethyl acetate to lOOS ethanol over 6ilica gel to yield 5.60 g of a light yellow 601id. Recry6tallization from acetonitrile yielded 4.36 g of light yellow cry6tal6 which 6till melted broadly. The cry6tal6 were taken up in 100 mL of hot acetonitrile. The 601id that did not di6601ve was filtered off to yield 1.04 g of product as a light yellow solid: m.p. 183.5-184.5.
Upon cooling, the mother liquor yielded an additional 1.03 g of product a6 a light yellow 601id; m.p.
179.0-180Ø NMR (200 MHz, DMSO-d6) ~ 7.75-7.48 (m, 4H): 7.07 (d, 2H, J= 9Hz); 7.04 (d, 2H, J= 9Hz):
5.24 (s, 2H): 5.24 (b6, lH): 4.34 (6, 2H); 2.48 (t, 2H, J= 7Hz): 1.48 (t of t, 2H, J= 7,7Hz); 1.27 (t of q, 2H, J= 7,7Hz); 0.81 (t, 3H, J= 7Hz). Anal. Calcd.
for C22H23ClN60: C, 62.48; H, 5.48; Cl, 8.38.
~ound for the 601id6 which did not di6601ve in 100 mL
of acetonitrile: C, 62.73; H, 5.50; Cl, 8.26. ~ound for the 601id6 obtained from the mother liguor: C, 62.40; H, 5.23: Cl, 8.35.
161 1 334~2 Example 90 PART A: Preparation of 2-n-Butyl-4-chloro-5-chloro-methyl-l-t(2'-cyanobiphenyl-4-yl)methyl]-imidazole-HCl salt 2-n-Butyl-4-chloro-5-hydroxymethyl-1-[(2'-cyanobiphenyl-4-yl)methyl~imidazole (15.00 q, 39.3 mmol, 1 eq) was converted to the chloride by the procedure in Example 1, Part B. The reaction time was 5 hours. The crude solid product wa~ was~ed with ether to remove the yello~ color. The solid white powdery product wa6 then dried under high vacuum, yield 10.02 9; m.p. 152.0-154Ø NHR (200 MHz, CDC13) ~ 7.85-7.46 (m, 6H): 7.20 (d, 2H, J,lOHz);
5.47 (8, ZH); 4.50 (6, 2H): 3.06 (t, 2H, J~ 7Hz): 1.82 (t of t, 2H, J= 7,7Hz): 1.45 (t of q, 2~, J. 7,7Hz);
0.94 (t, 3H, J= 7Hz). Ma66 Calcd. for C22H21C12N3: 397.1113. Found: 397.1105.
PART B: Preparation of 2-n-Butyl-4-chloro-1-t(2~-cyanobiphenyl-4-yl)methyl]-5-(methoxymethyl)-imidazole 2-n-Butyl-4-chloro-5-chloromethyl-1-1(2'-cyano-biphenyl-4-yl)methyl]imidazole-HC1 6alt (5.00 g, 11.5 mmol, 1 eq), 60dium methoxide (1.37 g, 25.3 mmol, 2.2 eq) and methanol (100 mL) were mixed and stirred for 3 days. The solvent was removed in vacuo and ethyl acetate (200 mL) and water (200 mL) added. The layer6 were separated and the aqueous layer was extracted with ethyl acetate (2 x 200 mL). The organic layer6 were dried (MgS04), the 601vent removed in vacuo and the re8idue flash c~romatographed over silica gel in 1:1 hexane/ethyl acetate to yield 4.06 g of a clear light yellow oil. NMR (200 MHz, CDC13) ~ 7.B2-7.43 (m, 6); 7.10 (d, 2H, J= 7Hz):
5.23 (s, 2H); 4.32 (s, 2H); 3.30 (s, 3H): 2.60 (t, 2H, 162 1 3340~2 J= 7Hz); 1.70 (t of t, 2H, J= 7,7Hz); 1.38 (t of q, 2H, J= 7,7Hz): 0.89 (t, 3H, J= jHZ). Anal. Calcd. for C23H24ClN30: C, 68.11; H, 6.54; Cl, 9.58.
Found: C, 68.70; H, 6.11; Cl, 9.51. Ma~s Calcd. for C23H24ClN30: 3g3.1607. Found: 393.1616.
PART C: Preparation of 2-n-Butyl-4-chloro-5-methoxy-methyl-l-t(2~-(lH-tetrazol-5-yl)biphenyl-4-methYl~imidazole 2-n-Butyl-4-chloro-1-~2~-cyanobiphenyl-4-yl)methyl]-5-methoxymethyl)imidazole (3.94 g, 10 mmol, 1 eq), ~odium azide (1.95 g, 30 mmol, 3 eq), and ammonium chloride (1.60 g, 30 mmol, 3 eq) were mixed and 6tirred in DMF (150 mL) in a round bottom fla~k connected to a ref 1UY condenser under N2. An oil bath with a temperature controller wa~ then u~ed to heat the reaction at 100C for 2 days, after which the temperature was rai~ed to 120C for 6 day6. The reaction was cooled and 3 more equivalent6 each of ammonium chloride and ~odium azide were added. The reaction was again heated for 5 more day~ at 120C.
The reaction was cooled, the inorganic ~alts filtered, and the filtrate solvent removed in vacuo. Water (200 mL) and ethyl acetate (200 mL) were added to the residue and the layers were 6eparated. The aqueous layer was extracted with ethyl acetate (2 x 200 mL), the organic layers were collected, dried (MgS04) and the 601vent removed in vacuo, to yield a dar~ yellow oil. ~lash chromatography in 100% ethyl acetate yielded 3.54 g of a white qla~s. NMR (200 MHz, CDC13) ~ 7.83 (d, lH, J= 7Hz): 7.59 (t, lH, J=
7Hz); 7.50 (t, lH, J= 7Hz): 7.39 (d, lH, J= 7Hz): 7.03 (d, 2H, J= 8Hz); 6.73 (d, 2H, J= 8Hz); 5.0B (s, 2H);
4.12 (6, 2H): 3.18 (s, 3H); 2.32 (t, 2H, J= 7Hz); 1.52 (t of t, 2H, J= 7,7Hz); 1.28 (t of q, 2H, J= 7,7Hz);
0.83 (t, 3H, J= 7Hz). Ma66 Calcd. for C23H25ClN60:436.1178. ~ound: 436.1750.
CAUTION~ The above reaction althougb uneventful in our S hand6 can be potentially explosivel Crystals that sublimed and collected in the reflux condenser during the reaction were not analyzed, but potentially could be ammonium azide~ Hydrazoic acid, which is shoc~
6en6itive, could al60 be potentially produced during the reaction and wor~-up. Extreme care should be taken~
ExamPle 91 5 PA~T A: Preparation of 2-butyl-4(5)-hydroxymethyl-5(4)-nitroimidazole To a solution of 5.75 g of 2-butyl-4(5)-hydroxymethylimidazole (prepared as de6cribed in U.S.
4,355,040) in 200 mL of aqueous methanol at 25C was added concentrated hydrochloric acid until the pH of the solution reached pH 3. The solvent was then removed in vacuo, and the re6idue wa6 di6601ved in 100 mL of chloroform. To thi6 601ution at 25 was added dropwi6e 15.0 mL of tbionyl chloride, and the mixture was refluxed for 1 hour. After cooling, the solvent and exce66 thionyl chloride were removed in vacuo to provide a viscou6 yellow oil.
To a solution of 20 mL of concentrated sulfuric acid and 10 mL of concentrated nitric acid at -10 wa6 added a 601ution of the yellow oil, prepared above, in 10 mL of concentrated 6ulfuric acid. The re~ulting mixture was heated on a steam bath for 2 hours. After cooling, the reaction mixture wa~ poured onto water-ice, and the resulting emulsion was extracted with chloroform. The combined organic phases were 164 1 334 Oq2 wa6hed with water and brine, dried over anhydrou6 ~ ~60dium 6ulfate, filtered, and concentrated in vacuo.
The residue was then di6601ved in 100 mL of 1:12-propanol/water. The 601ution wa6 then refluxed 5 for 16 bour~. Finally, after cooling, the colution wa6 concentrated in vacuo. Column chromatoqraphy (elution: methanol~chloroform) afforded 2.64 g of 2-butyl-4(5)-hydroxymethyl-5(4)-nitroimidazole. NMR
(200 MHz, DMS0-d6): ~ 12.92 (br 8, lH); 5.80 (br t, lH); 4-82 (d, 2H): 2.60 (t, 2H); 1.61 (quint., 2H):
1.25 (6ext., 2H): 0.84 (t, 3H).
PART B: Preparation of 1-~(2'-tert-butoxycarbonyl-biphenyl-4-yl)methyl~-2-butyl-5-hydroxy-methYl-4-nitroimidazole Thi6 compound wa6 prepared according to the procedure de6cribed in Example 85, Part C. From 2.64 g of 2-butyl-4(5)-hydroxymethyl-5(4)-nitroimidazole and 5.55 g of tert-butyl 4'-bromomethylbipbenyl-2-carboxylate there wa6 obtained 2.05 g of 1-t(2'-tert-butoxycarbonylbiphenyl-4-yl)methyll-2-butyl-5-hydroxy-methyl-4-nitroimidazole. NMR (200 MHz, CDC13): ~
7.79 (d, lH): 7.45 (m, 2H): 7.33 (d, lH): 7.28 (d, lH); 7.03 (d, 2H): 5.34 (6, 2H): 4.87 (6, 2~): 2.81 (br 6, lH): 2.67 (t, 2H): 1.73 (guint., 2H): 1.37 (6ext. 2H): 1.27 t6, 9H): 0.90 (t, 3H).
PART C: Preparation of l-t(2'-carboxybiphenyl-4-yl)-methyl]-2-butyl-5-bydroxymethyl-4-nitroimidazole A 601ution of 1.98 g Of lt(2'-tert-butoxy-carbonylbiphenyl-4-yl)methyl]-2-butyl-5-hydroxymethyl-4-nitroimidazole, 20 mL of trifluoroacetic acid, and 20 mL of methylene chloride wa6 6tirred at 25 for 1 hour. At thi6 point, the 601ution wa6 poured into water. The resulting mixture was adjusted to pH 3 using 10% 60dium hydroxide solution and then extracted with chloroform. The combined organic pba6es were washed with brine, dried over anhydrous magne6ium 6ulfate, filtered, and concentrated in vacuo. Column chromatography (elution: methanol~chloroform) provided 1.49 g of 1-t(2'-carboxybiphenyl-4-yl)-methyl]-2-butyl-S-hydroYymethyl-4-nitroimidazole: m.p.
204-205.5. NMR (200 MHz, DMS0-d6): ~ 7.71 ~d, lH); 7.56 (t, lH): 7.43 (t, lH): 7.32 (m, 3H): 7.15 (d, 2H): 5.63 (br 6, lH): 5.42 (6, 2H): 4.83 (6, 2H):
2.54 (t, 2H): 1.50 (quint., 2H): 1.24 (sext., 2H):
0.76 (t, 3H).
ExamPle 92 PART A: Preparation of l-t(2'-tert-butoxycarbonyl-biphenyl-4-yl)methyl]-2-butyl-4-iodo-5-(2-methoxYethoxymethoxymethyl~imidazole To a solution of 5.56 mL of 1.6 M n-butyl-lithium/hexane in 80 mL of tetrahydrofuran at 0 wa6 added dropwi6e 1.15 mL of t-butanol. To the solution was added 3.28 g of 1-~(2'-tert-butoxycarbonylbiphenyl-4-yl)methyl]-2-butyl-5-hydroxymethyl-4-iodoimidazole followed by 1.15 mL of 2-methoxyethoxymethyl chloride. The resulting solution wa6 6tirred at 25 for 16 hour6. The mixture was diluted wit~ diet~yl ether, washed with water and brine, dried over anhydrou6 60dium sulfate, filtered and concentrated.
Column chromatography afforded 2.61 g of 1-[2'-tert-butoxycarbonylbiphenyl-4-yl)methyl]-2-butyl-4-iodo-5-(2-methoxyethoxymethoxymethyl)imidazole. NMR
(200 MHz, CDC13): ~ 7.78 (d, lH): 7.43 (m, 2H);
7.28 (m, 3H); 6.98 (d, 2H): 5.26 (s, 2H); 4.69 (s, 2H); 4.45 (s, 2H): 3.68 (m, 2H); 3.57 (m, 2H); 3.37 (s, 3H); 2.58 (t, 2H); 1.67 (quint., 2H); 1.3q (sext., 2H); 1.26 (s, 9H): 0.87 (t, 3H).
-PART B: Preparation of l-t(2'-tert-butoxycarbonyl-biphenyI-4-yl)methyl~-2-butyl-5-(z-methoxy- ---ethoxymethoxymethyl)-4-trifluoromethyl-imidazole To a su6pension of 22.4 g of cadmium powder powder in 50 mL of dimethylformamide at 25 was added dropwi6e 8.60 mL of bromochlordifluoromet~ane. The resulting mixture was stirred at 25 for 2 hours and then was filtered through a medium-fritted Schlen~
funnel under nitrogen pressure to provide a dar~ brown 601ution of t~e trifluoromethyl cadmium reagent.
To a mixture of 15 mL of the above 601ution and 20 mL of hexamethylphosphoric triamide at 0 wa6 added 2.10 g of copper(I)bromide followed by 2.61 g of 1-t(2'-tert-butoxycarbonylbiphenyl-4-yl)methyl~-2-butyl-4-iodo-5-(2-methoxyethoxymethoxymethyl)imidazole in 5 mL of dimethylformamide. The reaction mixture was stirred at 70-75 for 6 hours. After cooling, t~e mixture wa6 diluted with water and then extracted with methylene chloride. The combined organic phases were washed with water and brine, dried over anhydrous 60dium 6ulfate, filtered, aDd concentrated. Column chromatography (elution: ethyl acetate/hexane) afforded 2.30 9 of 1-t(2'-tert-butoxycarbonylbiphenyl-4-yl)methyl~-2-butyl-5-(2-methoxyethoxymethoxymethyl)-4-trifluoromethylimidazole. NMR (200 ~Hz, CDC13):
7.79 (d, lH): 7.46 (m, 2H): 7.28 (m, 3H): 7.00 (d, 2H); 5.28 (6, 2H); 4.71 (s, 2H): 4.5B (s, 2H): 3.66 (m, 2H); 3.54 (m, 2H): 3.38 (8, 3H): 2.62 (t, 2H):
1.70 (quint., 2H): 1.36 (sext., 2H): 1.27 (s, 9H);
0.88 (t, 3H).
PART C: Preparation of l-t(2'-carboxybiphenyl-4-yl)-methyll-2-butyl-5-hydroxymethyl-4-trifluoro-methylimidazole A solution of 2.30 9 of 1-~(2~-tert-butoxy-carbonylbiphenyl-4-yl)methyl]-2-butyl-5-(2-methoxy-167 I 3340~2 ethoxymethoxymethyl)-5-trifluoromethylimidazole in 200 mL of 1.5 M aqueous tetrafluoroboric acid/acetonitrile was stirred at 25 for 18 hours, and then the mixture was poured into water. The resulting aqueous solution was adjusted to pH 3 employing saturated sodium bicarbonate solution and then was extracted with chloroform. The combined organic phases were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated. Column chromatography (elution: methanol/chloroform) provided 1.38 g of l-t(2l-carboxybiphenyl-4-yl)methyl]-2-butyl-5-hydroxy-methyl-4-trifluoromethylimidazole (m.p. 198-199.5).
NMR (200 MHz, DMS0-d6): ~ 7.75 (d, lH); 7.54 (t, lH); 7.43 (t, lH); 7.32 (m, 3H); 7.10 (d, 2H); 5.36 (s, 2H); 4.51 (s, 2H); 2.56 (t, 2H); 1.56 (quint., 2H); 1.30 (sext., 2H); 0.83 (t, 3H).
Example 93 PART A: Preparation of 4-azidomethyl-2'-methoxy-carbonYlbiphenyl To a stirred solution of 4-bromomethyl-2'-methoxycarbonylbiphenyl (150 g, 0.49 mol) in dry DMF
(500 ml) was added NaN3 (80 g, 1.23 mol, 2.5 eq).
The mixture was stirred at room temperature overnight (ca. 18 hours), filtered, and the filtrate was partitioned between ethyl acetate and H20 (500 ml each). The organic phase was washed twice more with H20, once with saturated aqueous NaCl solution and dried over anhydrous magnesium sulfate before being filtered and concentrated to leave 111.3 g (85%) of a yellow oil, used in the following step without further purification. NMR (CDC13, TMS, ~) 7.9-7.1 (m, 8H); 4.35 (s, 2H): 3.55 (s, 3H) IR Vmax 2487 cm 1, PART B: Preparation of 4-aminomethyl-2~-methoxy-carbonylbiPhenYl hYdrochloride The azido compound prepared above was di6solved in liter of methanol. The 601ution was divided into three equal volumes and placed in 500 ml Parr bottles.
To each flask was added 6.7 g of 5% Pd on carbon (Caution: Pyrophoricl add under a N2 atmosphere).
The fla6ks were 6ha~eD on a Parr hydroqenator under 40-50 psi H2 for 4-5 hour6 (oYernight i6 al60 acceptable). The mixture was ~uction filtered through a bed of Celite~ and the filtrate was concentrated to leave a vi6cou6 yellow re6idue (88 g). This wa6 di6solved in EtOAc (500 ml) to which wa6 added with ~tirring a solution of EtOAc ~aturated with an~ydrous HCl (100-150 ml) until precipitation wa6 complete.
The amine hydrochloride as produced wa6 6uction filtered, washed with EtOAc and hexane6 and dried under vacuum to afford 48.5 g (40% overall from the bromide) white solid: m.p. 204-208. NMR (CDC13,-CD30D; TMS) ~ 7.9-7.25 (m, 8H); 4.2 (6, 2H);
4.1-3.8 (br, 3H; 6hifts in D2O); 3.6 (6, 3H). HRMS
calcd. for C15H15NO2 (free base); M/Z 241.1103;
Found: M/Z: 241.1045.
PART C: Preparation of 1-[(2'-carboxybiphenyl-4-yl)-methyl~-2-PropYlthio-s-hydroxymethylimidazole The title compound wa6 prepared from methyl 4'-aminomethylbipbenyl-2-carboYylate by the procedures described in Example6 72, A and B, and 85E; m.p.
194-195.
The 4-biphenylmethyl compounds in Table 6 were prepared or could be prepared by the procedure6 illustrated in Examples 85-92 or by procedures previously described.
Table 6 1 334092 N ~
R6~N ~R8 ~ - QR13 No. R R7 R X ~ MP(-C) 94 n-butyl Cl CH20H 4 ~ 168-169.5 95 n-butyl CH20H Cl 4 ~ ~ 197-198 96 n-butyl H CH20H 4 ~ 154-155 C ~ (amorphous 97 n-butyl H CH20H 4 ~ solid) 98 n-butyl Cl CH20CH3q ~ 166.5-169.0 99 n-bu~yl Cl CH2OCH(CH3)2 4 ~ 156-158 Table 6 (continued) 1 3 ~ 4 0 9 2 ~ R
Ex 6 _ _ HP(-C) _ - C02H
100 n-butyl Br CH20H 4 ~ 175-178 C~
101 n-butyl F CH20H 4 ~
Co2H
102 n-butyl I CH20H 4 ~ 165 (dec) C~
103 OCH2 Cl CH20H 4 C~
104 ~ C1 CH20H 4 ~3 c~
105 n-butyl CH20H I 4~ 205 (dec) 106 n-butyl Cl CH20H 4 ~ 185-186 107 ethyl Cl CH20H 4~ 153-156 T~ble 6 (continued) 1 3 3 4 0 9 2 _~R 1 3 No. R R R ~P(-C) 108 n-propyl Cl CH2OH 4 ~ 198-200 109 n-pentyl Cl CH2OH 4 ~ (amorphous ~ ~olid) 110 n-hexyl Cl CH2OH 4 ~ 84-88 Co2H
111 n-butyl Cl CH2SH
Co2H
112 n-bu-yl Cl CH2O
Table 6 (continued) I 33409~
~R13 Ex. 6 R R X ~ HP(C) N-N
113 n-propyl Cl CH20H 4 ~ (amorphous solid) I \
~ ~ ~H
114 n-propyy Cl CHO 4 ~ (amorphous ~ solid) 115 n-butyl Cl CH2C02H 4 ~ ~ 221-222 116 n-butyl Cl CH(CH3)C02H 4 ~ 118-120 C~02H
117 n-butyl CH20H N02 4 ~ 154-157 /N-N
N~,NH
118 n-butyl CH OH Cl ~ (white 2 4 ~ \~ powder) N-N
N~,NH
119 n-buty~. No2 CH20H
T~hle 6 (continued) l 3 3 4 Oq 2 E~_ R6 Rl R8 ~ R13 MP (C) 120 n-butyl Cl N-N NN~
121 n-butyl Cl CH20COCH3 C02H 157-159 122 n-butyl Cl ~ CO2H
CH2OCOCH2CH2 <j=j~ _~
123 N-C4HgS H CH20H C ~H 190-191 4 ~
CH2S H CH20H ~ 1995 5-a -NMR (200 MHz, DMSO-d,) ~ 7.69 (dd, lH);
7.54 (d of t, lH)j 7.43 (d of t, lH); 7.33 (d, lH); 7.16 (A2B2, 4H); 6.76 (s, lH);
5.24~(s, 2H); 4.34 (s, 2H); 2.50 (t, 2H);
1.49 (quint, 2H); 1.25 (sext, 2H); 0.80 (t, 3H) 1 3343q2 b -NMR (200 MHz, DMSO-d6) ~ 7.70 (d, lH), 7.55 (t, lH), 7.42 (t, lH), 7.28 (m, 3H), 7.10 (d, 2H), 5.28 (~, 2H), 4.34 (~, 2H), 2.49 (t, 2H), 1.49 (m, 2H), 1.18 (m, 4H), 0.79 (t, 3H).
c -NMR (200 MHz, CDC13~CD30D): ~
7.82-6.93 (m, 8H): 5.21 (~, 2H): 4.47 (~, 2H): 2.55 (t, J= 7.5bz, 2H): 1.70-1.59 (m, 2H): 0.92 (t, J= 7.5 ~z, 3H).
d -NMR (200 MHz, CDC3) 9.65 (~, lH):
7.95-6.96 (m, 8H): 5.51 (~, 2H): 2.59 (t, J-7.5 hz, 2H): 1.70-1.63 (m, 2H): 0.92 (t, J=
7.5 hz, 3H).
e -NMR (Z00 MHz, CDC13) ~ 7.76 (d, lH, J=
7Hz): 7.57 (t, lH, J. 7Hz): 7.49 (t, lH, J=
7Hz): 7.40 (d, lH, J= 7Hz): 7.02 (d, 2H, J=
8Hz): 6.81 (d, 2H, J= 8Hz): 5.03 (~, 2H):
4.28 (~, 2H): 2.46 (t, 2H, J= 7Hz): 1.47 (t of t, 2H, J= 7,7Hz): 1.17 (t of q, 2H, J=
7,7Hz): 0.73 (t, 3H, J= 7Hz).
Example 125 Preparation of 1-[(2'-Carboxybiphenyl-4-yl)methyl]-2-butyl-4-chloroimidazole-5-carboxaldehYde A mixture of 1.46 g of 1-[2'-carboxybiphenyl-4-yl)methyl]-2-butyl-4-chloro-5-hydroxymethylimidazole and 7.30 g of activated mangane~e dioxide in 40 ml of tetrahydrofuran was ~tirred at 25C for S day6. The mixture wa~ filtered through Celite~, and the filtrate wa~ concentrated in vacuo. Column chromatography on 6ilica gel (elution: 2-10~ methanol/-chloroform) followed by recrystallization from ethyl acetate afforded 0.71 g of 1-t(2'-carboxybiphenyl-4-yl)methyl]-2-butyl-4-chloroimidazole-5-carboxaldehyde (m.p. 154-158C (dec.)). NMR (200 MHz, DMSO-d6) ~
12.85 (br 8, lH), 9.77 (~, lH), 7.77 (d, lH), 7.62 (t, lH), 7.50 (t, lH), 7.40 (d. lH), 7.26 (A2B2, 4H), 5.67 (8, 2H), 2.70 (t, 2H), 1.56 (quint., 2H), 1.28 (6ext., 2H), 0.83 (t, 3H).
Example 126 1 Preparation of Methyl l-t(2'carboYybiphenyl-4-yl)-methYl~-2-butYl-4-chloroiraidazole-5-carboxylate To a mixture of 1.45 g of 1-t(2'-carboxybiphenyl-4-yl)methyl]-2-butyl-4-chloroimidazole-5-carboxaldehyde and 0.91 g of sodium cyanide in 20 ~L of methanol at 25C wa~ added 0.32 mL of acetic acid followed by 7.25 g of mangane6e dioxide. The re~ulting mixture was stirred at 25C for 40 hours. The reaction mixture wa~ filtered through Celite~, and the filtrate diluted with water. The aqueous solution wa~ adju6ted to pH 3 u~ing hydrochloric acid and extracted with methylene chloride. The combined organic pha~e6 were wa~hed with brine, dried over anhydrou~ sodium sulfate, filtered, and concentrated. The crude product was recry6tallized from diethyl ether to afford 0.90 g of methyl 1-t(2'-carboxybiphenyl-4-yl)-methyl]-2-butyl-4-chloroimidazole-5-carboxylate (m.p.
154-155C). NMR (200 MHz, DMS0-d6): ~ 12.75 (br 8, lH), 7.73 (d, lH) 7.58 (t, lH), 7.46 (t, lH), 7.34 (m, 3H), 7.07 (d, 2H), 5.63 (6, 2H), 3.78 (8, 3H), 2.67 (t, 2H), 1.56 (quint., 2H), 1.29 (sext., 2H), 0.83 (t, 3H).
-Example 127 1 3 3 4 0 q 2 Preparation of l-t(2'-Carboxybiphenyl-4-yl)methyl]-2-butyl-4-chloroimidazole-5-carboxamide Anhydrous ammonia was bubbled into 40 mL of i-propanol until the solvent was saturated. To this solution at 25C was added 0.49 g of powdered sodium cyanide, then O.B0 g of 1-~(2'-carboxybiphenyl-4-yl)-methyl]-2-butyl-4-chloroimidazole-5-carboxaldehyde, and finally 3.48 g of mangane~e dioxide. Thi6 mixture 10 was stirred at 25C for 65 hour6. The reaction mixture was filtered through Celite~, and the filtrate concentrated in vacuo. The re~idue was dis601ved in water, and the aqueous solution was adjusted to pH 3 usinq hydrochloric acid and then extracted with methylene chloride. The combined organic phases were wa6hed with brine, dried over anhydrous sodium ~ulfate, filtered, and concentrated.
Column chromatography on silica gel (elution: 0-10%
i-propanol (chloroform) provided 0.22 g of l-t(2'-carboxybiphenyl-4-yl)methyl]-2-butyl-4-chloroimidazole-5-carboxamide as a white 601id (m.p. 200-202C). NMR
(200 MHz, DMSO-d6): ~ 12.74 (br s, lH); 7.71 (d, 2H); 7.56 (t, lH), 7.48-7.30 (m, 6H): 7.09 (s, 2H):
5.57 (s, 2H): 2.59 (t, 2H): 1.51 (quint., 2H): 1.26 (sext. 2H): 0.80 (s, 3H).
ExamPle 128 PA~T A: Preparation of l-t(2'-Carbomethoxybiphenyl-4-- yl)methyl]-2-butyl-4-chloroimidazole-5-carboxaldehyde A mixture of 2.06 g of 1-t(2'-carbomethoxy-bip~enyl-4-yl)methyl]-2-butyl-4-chloro-5-hydroxymethyl-imidazole and 3.08 g of activated manganese dioxide in 20 mL of methylene chloride at 25C was stirred for 40 hours. The reaction mixture was filtered through ~
Celite~, and the filtrate concentrated in vacuo.
Column chromatography (elution: ethyl acetate/benzene) provided 1.15 g of 1-1(2'-carbo-methoxybiphenyl-4-yl)methyll-2-butyl-4-chloro-imidazole-5-carboxaldehyde. NMR (200 MHz, CDC13) 9.76 (s, lH); 7.83 (d of d, lH); 7.52 (t of d, lH); 7.40 (t of d, lH); 7.31 (d of d, lH); 7.17 (A2B2, 4H); 5.58 (8, 2H); 3.63 (8, 3H); 2.67 (t, 2H); 1.70 (quint., 2H); 1.38 (sest., 2H); 0,90 (t, 3H).
PART B: Preparation of 1-~(2-Carbomethoxybiphenyl-4-yl)methyl]-2-(1-bromobutyl)-4-cbloroimidazole-5-carboxaldehYde A mixture of 1.12 g of l-t(2~-carbometboYybi-phenyl-4-yl)methyl]-2-butyl-4-chloroimidazole-5-carboxalde~yde and 0.49 g of N-bromosuccinimide in 40 mL of CC14 was irradiated (W-lamp, pyrex filter) for 0.5 ~our6. The reaction mixture wa~ filtered, and the filtrate was concentrated in vacuo. Column chromatograpby (elution: ethyl acetate/benzene) afforded 0.54 g of 1-~(2'-carbomethoxybiphenyl-4-yl)-methyl]-2-(1-bromobutyl)-4-chloroimidazole-5-carbox-aldehyde. NNR (200 MHz, CDC13) ~ 9.87 (6, lH);
7.86 (d, lH): 7.5g (t, lH); 7.46 (t, lH): 7.30 (m, 3H); 7.11 (d, 2H); 6.16 (d, lH); 5.32 (d, lH); 4.79 (t, lH); 3.65 (6, 3H): 2.32 (m, 2H): 1.34 (sext., 2H);
0.83 (t, 3H).
PART C: Preparation of l-t(2'-Carbomethoxybiphenyl-4-yl)methyl]-2-(1-trans-butenyl)-4-chloro-imidazole-5-carboxaldebYde A 601ution of 0.54 g of 1-1(2'-carbomethoxy-biphenyl-4-yl)methyl]-2-(1-bromobutyl)-4-chloro-imidazole-5-carboxaldehyde and 0.33 mL of 1,8-35 diazabicyclol4.5.0]undec-7-ene in 10 mL of tetrahydrofuran was 6tirred at 25C for 18 hour6. the reaction mixture was diluted with diethyl ether, wa6hed with dilute hydrochloric acid, water, and brine, dried over anhydrous 60dium 6ulfate, filtered, and concentrated in vacuo. Column chromatography (elution:ethyl acetate/benzene) furni6hed 0.26 g of ~ 2'-carbomethoxybiphenyl-4-yl)methyl]-2-(l-tran6-butenyl)-4-chloroimidazole-S-carboxaldehyde. NMR (200 MHz, CDC13~ ~ 9.75 (6, lH); 7.82 (d, lH); 7.51 (t, lH); 7.40 (t, lH); 7.33-7.07 (m, 6H); 6.27 (d, lH);
5.62 (6, 2H): 3.62 (6, 3H): 2.30 (quint., 2H); 1.09 (t, 3H).
PART D: Preparation of l-t(2'-Carbomethoxybiphenyl-4-yl)methyl~-2-(l-tran6-butenyl)-4-chloro-S-hydroxymethylimidazole To a 601ution of 0.26 g of 1-[(2'-carbomethoxybi-phenyl-4-yl)methyll-2-(l-tran6-butenyl)-4-chloro-imidazole-S-carboxaldehyde in 10 mL of methanol at 0C
wa6 added 0.24 g of 60dium borohydride portionwi6e over O.S hour6. The mixture wa6 6tirred for an additional 0.5 hour6 at 0C and then poured into a 601ution at 10% 60dium hydroxide in water. The resulting mixture was extracted with ethyl acetate, and the combined orqanic pha6e6 were wa6hed with brine, dried over anhydrou6 60dium 6ulfate, filtered, and concentrated in vacuo. Column chromatography (elution:ethyl acetate/benzene) provided 0.23 g of l-t2~-carbomethoxybiphenyl-4-yl)methyl-2-(l-tran6-butenyl)-4-chloro-5-hydroxymethylimidazole. NMR (200 MHz, CDC13) ~ 7.84 (d, lH); 7.53 (t, lH): 7.40 (t, lH): 7.29 (m, 3H): 7.08 (d, 2H): 6.86 (d of t, lH):
6.17 (d, lH): 5.30 (6, 2H): 4.54 (br 6, 2H): 3.63 (6, 3H): 2.23 (quint., 2H); 1.04 (t, 3H).
- 1 3340~2 PART E: Preparation of l-t(2~-carboxybiphenyl-4-yl) methyl~-2-(1-trans-butenyl)-4-chloro-5-hydroxymethylimidazole Thi~ compound was prepared according to theprocedure de6cribed in Example 85, Part E. From 0.23 g of l-t(2'-carbomethoxybiphenyl-4-yl)methyl~-2-(1-tran6-butenyl)-4-chloro-5-hydroYymethylimidazole there was obtained 0.16 g of 1-t(2'-carboxybiphenyl)-4-yl)methyl~-2-(l-tran6-butenyl)-4-chloro-5-hydroxy-methylimidazole (m.p. 198.5-199.5C). NMR (200 MH2, DMS0-d6) ~ 7.71 (d, lH): 7.56 (t, lH): 7.44 (t, lH): 7.32 (m, 3H): 7.11 (d, 2H): 6.62 (d of t, lH):
6.39 (d, lH): 5.38 (8, 2H); 5.33 (br 6, lH): 4.35 (br 6, 2H); 2.18 (quint., 2H); 0.99 (t, 3H).
ExamPle 129 Preparation of l-t(2'-Carboxybiphenyl-4-yl)methyl]-2-(l-tran6-butenYl)-4-chloroimidazole-5-carboxaldehyde Thi6 compound was prepared according to the procedure of Example 125. From 0.50 g of 1-t(2'-carboxybiphenyl-4-yl)methyl~-2-(1-trans-butenyl)-4-chloro-S-hydroxymethylimidazole and 2.50 g of mangane6e dioxide wa6 obtained 0.24 g of 1-t(2'-carboxybiphenyl-4-yl)methyl~-2-(l-tran6-butenyl)-4-chloroimidazole-5-carboxaldehyde (m.p. 164-166C).
NMR (200 MHz, DMS0-d6) ~ 12.79 (br 6, lH); 9.70 (s, lH); 7.72 (d, lH); 7.57 (t, lH); 7.46 (t, lH);
7.33 (m, 3H); 7.15 (d, 2H), 7.01 (d of t, lH); 6.65 (d, lH); 5.71 (8, 2H); 2.28 (quint., 2H); 1.04 (t, 3H).
180 l 334092 The compounds in Table 7 were prepared or could be prepared empioying the procedures described in Examples 125-129 or by procedures described previously.
Table 7 N
R6~N ~
~ ~ - Rl3 .. R13 Ex. ~
No. R6 R7 R8 MP(C) 130 n-butyl H CHO 4- ~ (amorphousa solid) 131 n-butyl CF3 CHO 4- ~ 132-134 ~N~
N ~ 127.5-131.5 132 n-butyl C1 CHO
N~N~NH
133 n-butyl CF3 CHO h~ (amorphous ~ solid)b ,. !~.
Table 7 (continued) Rl3 1 334092 x~
Ex.
No. R6 R' R3 MP(C) -- ,, C~
134 n-butyl C1 CONHCH3 4 ~ (solid) 135 n-butyl Cl CON(CH3)2 4 ~ (solid) 136 CH3CH=CH- C1 CH2OH 4 137 CH3CH2CH=CH- CF3 CH2OH 4 ~ 217-219 138 CH3CH2CH=CH- Cl CHO 4 ,N~
139 CH3Ch2CH=CH- Cl CH2OH N ~ (amorphoue solid ) , N~
N~
140 CH3CH2CH=CH- Cl CHO 4 a -NMR (200 MHz, DMSO-d6) ~ 12.76 (br 6, lH); 9.67 (6, lH): 7.93 (s, lH); 7.71 (d, lH); 7.55 (t, lH); 7.43 (t, lH); 7.30 (m, 3H); 7.06 (d, 2H); 5.63 (6, 2H); 2.67 (t, 2H); 2.57 (quint., 2H); 2.27 (6ext. 2H); 0.81 (t, 3H).
b -NMR (200 MHz, DMSO-d6) ~ 12.75 (br 6, lH); 8.10 (br ~uart., lH); 7.72 (d, lH); 7.57 (t, lH); 7.45 (t, lH); 7.32 (m, 3H); 7.10 (d, 2H): 5.51 (6, 2H); 2.75 (d, 3H); 2.58 (t, 2H);
1.52 (quint., 2H): 1.27 (6ext., 2H): 0.81 (t, 3H).
c -NMR (200 HHz, DMSO-d6) ~ 12.77 (br 6, lH): 7.73 (d, lH): 7.57 (t,lH); 7.45 (t, lH):
7.33 (m, 3H) 7.09 (d, 2H): 5.20 (br 6, 2H):
2.83 (6, 3H): 2.73 (t, 2H): 2.66 (6, 3H):
1.63 (quint., 2H): 1.36 (6ext., 2H): 0.89 (t, 3H).
-PART A: Preparation of l-t2'-Aminobiphenyl-4-yl)-methyl~-2-butyl-9-chloro-S-methoxymethyl-imidazole A 601ution of 4.40 g of 1-t(2~-nitrobiphenyl-4-yl)methyl]-2-butyl-4-chloro-5-methoxymethylimidazole, 2.10 g of iron powder, 4.25 mL of glacial acetic acid, and 200 mL of methanol wa6 refluxed for 5 hours.
After cooling, the solvent wa~ removed in vacuo, and the re6idue wa6 dis601ved in etbyl acetate. The precipitated iron 6alt6 were removed by filtration through Celite~, and the re6ulting 601ution was wa6hed with water and brine, dried over anhydrous sodium sulfate and concentrated. Column chromatograp~y 1 on 6ilica gel (elution: 10-30S ethyl acetate/benzene) furni6hed 2.95 g of 1-12'-aminobiphenyl-4-yl)methyl~-2-butyl-4-chloro-S-methoxymethylimidazole: NMR (200 MHz, CDC13): ~ 7.43 (d, 2H): 7.19-7.04 (m, 4H):
6.80 (m, 2H); S.l9 (8, 2H); 4.33 (8, 2H); 3.70 (br 8, lH); 3.28 (8, 3H); 2.59 (t, 2H); 1.67 (quint., 2H);
1.34 (6ext., 2H); 0.87 (t, 3H).
PART B: Preparation of l-t2'-Trifluoromethane6ul-fonamidobiphenyl-4-yl)methyl~-2-butyl-4-chloro-5-methoxYmethylimidazole To a solution of 2.95 g of 1-t(2'-aminobiphenyl-4-yl)methyl1-2-butyl-4-chloro-5-methoxymethylimidazole and 1.07 mL of triethylamine in 30 mL of methylene chloride at -78 wa6 added 2.59 mL of trifluoro-methane6ulfonic anhydride dropwise at such rate that the reaction temperature remain6 below -50. ~ol-lowing the addition, the reaction mixture wa6 allowed to warm 610wly to 25. At the point the mixture wa6 poured into dilute aqueous acetic acid. The resulting 6u~pension wa6 6tirred vigorou61y for several minutes and then extracted with methylene chloride. The combined organic pha6e6 were wa6hed with water and brine, dried over anhydrou6 60dium 6ulfate, filtered and concentrated. Column chromatography on silica gel (elution: 20-50% ethyl acetate/benzene) afforded 0.80 g of l-t(2~-trifluoromethane6ulfonamidobiphenyl-4-yl)-methyl]-2-butyl-4-chloro-5-methoxymethylimidazole, m.p. 148-150: NMR (200 MHz, CDC13): ~ 7.60 (d, lH): 7.44-7.27 (m, 5H): 7.07 (d, 2H): 5.20 (6, 2H):
4.29 (6, 2H): 3.27 (8, 3H): 2.57 (t, 2H): 1.65 (quint., 2H): 1.35 (6ext., 2H): 0.88 (t, 3H).
Example6 142 to 147 can or could be prepared by the procedure6 described in Example 141 u6ing the appropriate 6tarting material.
Table 8 N ~
S R6~N~R8 ~--R13 Ex No. R R R R MP(C) NHso2cF3 142 n-butyl H CH2OCH3 4 ~
143 n-~exyl Cl CH20CH3 4 ~
NHso2cF3 144 n-butyl Cl CH20H 4 ~ 171-172 145 FCH2CH2CH2CH2- Cl CH20H 4 ~
NHso2cF3 146 H02CCH2CH2CH2CH2- Cl CH20H 4 ~
NHso2cF3 3 2 2 2 Cl CH20H 4 186 1 3340~
Example 148 PART A: Preparation of 2-Butyl-l-t(2'-carbomethoxy-biphenyl-4-yl)methyl~-4-chloro-5-(chloro-methyl)imidazole-HCl salt 2-Butyl-1-~(2'-carbomethoxybiphenyl-4-yl)methyl]-4-chloro-5-(chloromethyl)imidazole-HC1 6alt va6 pre-pared from 2-butyl-1-~(2'-carbomethoxybiphenyl-4-yl)-methyl~-4-chloro-5-(hydroxymethyl)imidazole u6ing the procedure of Example 1, Part B: m.p. 156.0-161Ø
(200 ~Hz, CDC13) ~ 7.90 ~d, lH, 7Hz); 7.56 (t, lH, J= 7Hz); 7.45 (t, lH, J= 7Hz); 7.43-7.26 (m, 3H);
7.12 (d, 2H, J= 8Hz); 5.47 (6, 2H): 4.48 (6, 2H); 3.70 (s, 3H): 3.14 (t, 2H, J= 7Hz); 1.80 (t of t, 2H, J.
7,7Hz); 1.44 (t of q, 2H, J~ 7,7Hz); 0.92 (t, 3H, J~
7Hz). Anal. . 23 24 2 2 2 H, 5.39; N, 5.99. Found: C, 58.80; H, 5.48; N, 5.69.
Mas6 Calcd. for C23H24C12N202: 430.1215. Pound 430.1215.
PART B: Preparation of 5-Azidomethyl-2-n-butyl-1-~(2~-carbomethoxybiphenyl-4-yl)methyl~-4-chloroimidazole 2-Butyl-l-t(2'-carbomethoxybiphenyl-4-yl)methyl]-4-chloro-5-(chloromethyl)imidazole-HC1 salt (3.31 g, 7.67 mmol, 1 eq), 60dium azide (1.50 g, 23.0 mmol, 3 eq) and DMS0 (100 mL) were mixed and stirred over-night. Water wa6 then added (500 mL) and the aqueou6 extracted with ethyl acetate (3 ~ 300 mL). Tbe organic layer6 were dried (MgS04) and concentrated to yield 3.48 g of product a6 an oil. NMR (200 MHz, CDC13) ~ 7.85 (d, lH, J= 7Hz): 7.54 (t, lH, J= 7Hz);
7.40 (t, lH, J= 7Hz); 7.28 (d, 2H, J- 8Hz); 7.00 (d, 2H, J= 8Hz); 5.20 (6, 2H); 4.23 (8, 2H): 3.67 (8, 3H);
2.63 (t, 2H, J= 7Hz); 1.73 (t of t, 2H, J= 7,7Hz);
-1.39 (t of q, 2H, J= 7,7Hz): 0.91 (t, 3H, J= 7Hz).
Mass Calcd. for C23H24ClN5O2: 438.1697. Pound:
438.1669.
PART C: Preparation of 5-Aminomethyl-2-butyl-l-t(2'-carbomethoxybiphenyl-4-yl)methyl]-4-chloroimidazole 5-Azidomethyl-2-butyl-1-t(2'-carbomethoxybi-phenyl-4-yl)methyl]-4-chloroimidazole (3.48 g) was hydrogenated at 1 atm in methanol (100 mL) over 10%
palladium/carbon (0.5 q). After 1 ~our, the mixture was filtered through Celite~ and the solvent removea in vacuo to give product (2.80 q) a6 an oil. NMR (200 MHz, CDC13) ~ 7.84 (d, lH, J. 7Hz); 7.52 (t, lH, J= 7Hz): 7.40 (t, lH, J= 7Hz); 7.30 (d, lH, J- 7Hz);
7.26 (d, 2H, J= 8Hz): 7.02 td, 2H, Jz 8Hz): 5.27 (6, 2H); 3.74 (6, 2H); 3.65 (6, 3H); 2.60 (t, 2B, J. 7Hz);
1.67 (t of t, 2H, J= 7,7Hz); 1.36 (t of q, 2H, J.
7,7Hz): 0.86 (t, 3H, J= 7Hz). Anal. Calcd. for C23H26ClN3O2-(DMSO)o 5: C, 63.91: H, 6.48:
N, 9.32. ~ound: C, 63.78: H, 6.30: N, 9.14 PART D: Preparation of 5-Aminomethyl-2-butyl-1-[(2~-carboxybiphenyl-4-yl)methyl]-4-chloroimidazole 5-Aminomethyl-2-butyl-1-t(2'-carbomethoxybi-phenyl-4-yl)methyl]-4-chloroimidazole (1.64 g. 3.98 Dmol, 1 eq), O.5N KOH in ~ethanol (11.96 ~L, 5.98 mmol, 1.5 eq), water (1.0 mL) and methanol (20 mL) were mixed and refluxed under N2 overniqht. The 601ution wa~ then brought to neutrality with lN HCl and the 601vent6 removed in vacuo. The re6idue wa6 ta~en up in DM~ and the salt6 filtered off. T~e DMF
was then removed in vacuo to yield 1.76 g of a glass.
NMR (200 MHz, DMSO-d6) ~ 7.50 (d, lH, J= 7Hz):
lB7 1 33409~ -7.40-7.18 (m, 5H); 6.92 (d, 2H, J= 8Hz): 6.50 (bm, 3H); 5.26 (~, 2H); 3.60 (6, 2H); 2.55 (t, 2H, J= 7Hz);
1.51 (t of t, 2H, J= 7,7Hz); 1.27 (t of q, 2H, J=
7,7Hz); 0.81 (t, 3H, J= 7Hz).
PART E: Preparation of 2-Butyl-l-t(2'-carboxybi-phenyl-4-yl)methyl]-4-chloro-5-(ethoxy-carbonYlaminomethyl)imida2ole 2-Butyl-l-t(2'-carboYybip~enyl-4-yl)methyl]-4-chloro-5-(ethoxycarbonylaminomethyl)imidazole wa6 prepared from 5-aminomethyl-2-n-butyl-1-t(2~-carboxy-biphenyl-4-yl)methyl]-4-chloroimidazole u6ing ethyl chloroformate and the Schotten-Baumann procedure described in Example 209, Part B: m.p. 144.0-147Ø
1 NMR (200 MHz, DMS0-d6) ~ 12.74 (8, lH): 7.73 (d, lH, J= 7Hz); 7.63-7.27 (m, SH): 7.03 (d, 2H, J= lOHz):
5.27 (6, 2H); 4.60 (bd, 2H, J= 7Hz): 3.90 (q, 2H, J=
7Hz): 3.34 (6, 2H): 2.47 (t, 2H, J= 7Hz): 1.48 (t of t, 2H, J= 7,7Hz): 1.24 (t of q, 2H, J= 7,7Hz): 1.06 (t, 3H, J= 7Hz): 0.78 (t, 3H, J=7Hz). Anal. Calcd.
25 28ClN304-(H2o)o 33: C, 63.17; H, 6.06;
N, 8.83. Found: C, 63.30: H, 6.35: N, 8.44.
Example6 149-159 in Table 9 were prepared or could be prepared u6ing the appropriate chloroformate by the procedure de6cribed in Example 148, Part6 D and E (the order of which may be interchanged by one 6killed in the art) i.e., 6tarting with the amino e6ter from Part C, reacting it with a chloroformate under Schotten-Baumann type condition6 followed by hydrolyzing the e6ter if nece66ary.
Table 9 1 334092 N ~ 0 R6 ~ N ~ NHCOR
~ ~13 No. _ R _ R MP(C) 149 n-butyl Cl C6H5 C02H 198.0-200.0 150 n-butyl Cl CH3 CO2H 151.0-155.0 151 n-butyl Cl CH2CH2CH3 C02H 115.5-117.0 1 152 n-butyl Cl CH2(CH3)2 C02H 135.5-138.0 153 n-butyl Cl CH2CH2CH2CH3 C02H 123.0-125.0 154 n-butyl Cl l-adamantylC02H 170.0-172.0 155 n-propyl Cl CH3 C02H
156 n-butyl Cl CH3 ~ ~ 202.0-204.5 N-N
157 n-butyl Cl (CH2)2cH3 ~ N~N
N-N
158 n-propyl Cl CH3 ~ N,N
H
N-N
159 n-propyl H 2 3 ~ N,N
Examples 160-164 in Table 10 were prepared or could be prepared from 2-n-butyl-1-t(2'-carbomethoxybi-phenyl-4-yl)methyl]-S-chloro-4-(hydroxymethYl)imidazole using the procedures in Example 148.
Table 10 N ~ NHCO~
~6 ~ N ~ a8 ~
Ex 15 No. R6 R R R NP(C) 160 n-butyl Cl CH3 COOH 200-205 161 n-butyl 2 3 COOH
162 n-butyl Cl CH2CH2CH3 COOH 166.5-169.5 163 n-butyl Cl CH2CH2CH2CH3 COOH
164 n-butyl Cl CH(CH3)2 COOH
191 1 3340q2 PART A: Preparation of 2-n-Butyl-l-t(2'-carbomethoxy-biphenyl-4-yl)methyl]-4-chloro-5-(1-naphthyl-aminocarbonylaminomethyl)imidazole 5-Aminomethyl-2-butyl-1-t(2'-carbomet~oXybi-phenyl-4-yl)methyl)-4-chloroimidazole (1.00 g, 2.4 mmol, 1 e~) and l-napht~yl ~60cyanate (0.35 mL, 2.4 mmol, 1 eq), were mixed and ~tirre~ ~n c~loroform at room temperature for 3 day6. The 601vent wa~ removed in vacuo and the re6idue wa6 purified by flas~
chromatoqraphy over 6ilica gel in 1:1 ~exane/ethyl acetate to yield 770 mg of a white gla6s. NMR (200 MHz, CDC13) ~ 7.83 (d, 3H, J~ 6Hz): 7.67 (d, lH, J= 6Hz): 7.56-7.18 (m, 9H): 6.97 (d, 2H, J~ 7Hz): 6.74 (6, lH): 5.27 (6, 2H); 4.74 (6, lH): 4.39 (d, 2H, J=
7Hz): 3.58 (6, 3H); 2.60 (t, 2H, J= 7Hz): 1.43-1.21 (m, 4H): 0.85 (t, 3H, J= 7Hz).
PART B: Preparation of 2-n-Butyl-1-~(2~-carboxy-biphenyl-4-yl)methyl]-4-chloro-5-(1-naphthylaminocarbonylaminomethyl)-imidazole The title compound wa6 prepared from 2-n-butyl-1-t(2'-carbomethoxybiphenyl-4-yl)methyl]-4-chloro-5-(1-naphthylaminocarbonylaminomethyl)imidazole by the hydroly6i6 procedure de6cribed in Example 148, Part D. Work-up yielded 380 mg of white cry6talline 601id:
m.p. 169-175. NMR (200 MHz, DMSO-d6) ~ 8.45 (6, lH): 8.05-7.03 (m, 15H): 6.97 (6, lH): 5.34 (6, 2H):
4.30 (d, 2H, J= 5Hz): 2.52 (t, 2H, J= 7Hz): 1.48 (t of t, 2H, J= 7,7Hz): 1.21 (t of q, 2H, J= 7,7Hz): 0.85 (t, 3H, J= 7Hz). Anal. Calcd. for 33 31ClN43-(H2)0 5: C, 68.77 H
5.60; N, 9.70. Found: C, 68.88: H, 5.67; N, 9.70.
Examples 166-172 in Table 11 were prepared or could be prepared using the appropriate isocyanate by the procedure described in Example 165.
Ta~le 11 ~33409 ~
1 ~,H " H
R6 N 2~-C-N-R
~;
No R Cl CH3 C02H ~p(oC~
167 n-Bu Cl CH2 3 co2H
168 n-Bu Cl CH2cH2cH3 C0 H
169 n-Bu Cl CH2CH2CH2cH3C2H
170 n-Bu Cl CH(cH3~2 C0 H
171 ~-Bu Cl ~ co2n 163-166 172 n-Bu Cl l-adamantyl~ ,N
-194 l 3340q ~
ExamPle 173 Preparation of 2-n-Butyl-4-chloro-5-methoxymethyl-l-t(2'-((tetrazol-5-yl)aminocarbonyl)biphenyl-4-yl)-methyl~imidazole 2-n-Butyl-l-t(2'-carboxybiphenyl-4-yl)methyl]-4-chloro-5-(methoYymethyl)imidazole tl- g) wa6 fir6t converted to the corre~ponding acid chloride and then coupled to 5-aminotetrazole by the procedure in Example 78, Part C to yield 0.87 g of a yellow gla66.
Fla~h chromatography in 100% ethyl acetate over 6ilica qel yielded 77.1 mq of a white 601id: m.p. 169-173.
NMR (200 MHz, CDC13, DMS0-d6) ~ 12.0 (br 6, lH):
7.73-7.30 (m, 6H): 7.00 (d, 2H, J= 7Hz): 5.18 (6, 2H):
4.23 (6, 2H): 2.55 (t, 2H, Js 7Hz) 1.63 (t of t, 2H, J= 7,7Hz): 1.31 (t of q, 2H, J. 7,7Hz): 0.84 (t, 3H, J= 7Hz). Anal. Calcd. for C24H26ClN702-(H20)2:
C, 55.87; H, 5.86. Found: C, 56.01; H, 6.01.
Example 174 PART A: Preparation of 2-n-Butyl-4-chloro-1-~(2'-(hydroxymethyl)biphenyl-4-yl)methyl]-5-(methoxYmethyl)imidazole 2-n-Butyl~ 2'-carbomethoxybiphenyl-4-yl)-methyl]4-chloro-5-(methoxymethyl)imidazole l5.62 g, 13 mmol, 1 eq) wa6 di6601ved in TH~ (50 mL) and to it wa6 610wly added a lM lithium aluminum hydride 601ution in THF (39.5 mL, 39 mmol, 3 eq). The re6ultant mixture wa6 refluxed under N for 2 bours and wor~ed up according to Fie6er and Pie6er, V.l, p. 584 (Steinhardt procedure) to yield 4.68 q of a ligbt yellow oil which 610wly cry~tallized. NMR (200 HHz, CDC13) ~ 7.57 (bd, lH, J= 7Hz): 7.47-7.20 (m, 5H):
7.03 (d, 2H, J= 9Hz); 5.18 (8, 2H); 4.58 (6, 2H): 4.32 (6, 2H); 3.28 (6, 3H); 2.60 (t, 2H, J. 7Hz); 1.67 (t of t, 2H, J= 7, 7Hz); 1.35 (t of q, 2H, J. 7,7Hz):
0.86 (t, 3H, J= 7Hz). Anal. Calcd. for C23H27ClN2O2:
C, 69.25: H, 6.82: Cl, 8.89. Found: C, 69.42; H, 6.87; Cl, 8.65.
PART B: Preparation of 2-n-Butyl-4-chloro-1-t(2~-(cyanomethyl)biphenyl-4-yl)methyl~-5-(methoxymethYl~imidazole 2-n-Butyl-4-chloro-1-t(2'-(hydroxymethyl)-biphenyl-4-yl)methyl-5-(methoxymethyl)imidazole (4.68 g) wa6 converted to the title cyanomethyl compound by the procedure de6cribed in Example 1, Part B. Work up yielded 5.20 g of a brown oil which wa6 further reacted with purification. NMR (200 HHz, CDC13) ~
7.54 (m, lH); 7.40 (m, 2H); 7.28 (m, 3H); 7.08 (d, 2H, J= lOHz); 5.23 (6, 2H); 4.33 (s, 2H); 3.63 (6, 2H);
3.30 (6, 3H); 2.60 (t, 2H, J= 7Hz): 1.70 (t of t, 2H, J= 7,7Hz); 1.37 (t of q, 2H, J= 7,7Hz); 0.90 (t, 3H, J= 7Hz). Ma66 Calcd. for C24H26ClN30:
407.1764. Found: 407.1778.
196 l 334092 PART C: Preparation of 2-n-Butyl-4-chloro-5-methoxy-methyl-l-[(2'-((tetrazol-5-yl)methyl)bi-phenyl-4-Yl)methyl]imidazole 2-n-Butyl-4-chloro-1-t(2'-(cyanomethyl)biphenyl-4-yl)methyl~-5-(methoxymethyl)imidazole (5.20 g) was converted to the above tetrazole in 2 days usinq the procedure of Example 90, Part C. Wor~-up and fla6h chromatography over silica gel eluting with a gradient solvent sy6tem of 1:1 hexane~ethyl acetate to 1:1 ethyl acetate/i60propanol yielded 3.13 g of a light yellow ~olid; m.p. 149.0-152.5. NMR (200 MHz, CDC13) ~ 7.37-7.15 (m, 6H): 6.96 (d, 2H, Jz 9Hz):
5.18 (6. 2H); 4.30 (fi, 2H): 4.24 (6, 2H): 3.27 (8, 3H): 2.57 (t, 2H, J5 7Hz); 1.56 (t of t, 2H, J-1 7,7Hz); 1.28 (t of 9, 2H, J= 7,7Hz): 0.77 (t, 3H, J=
7Hz). Anal. Calcd. for C24H27ClN60: C, 63.97, H, 6.03: Cl, 7.86. Pound: C, 63.79: H, 6.04: Cl, 7.70.
ExamPle 175 20Preparation of 2-n-Butyl-l-t(2l-(carboxymethyl)bi-phenyl-4-yl)methyl]-4-chloro-5-(hydroxymethyl)-imidazole-dicyclohexylamine 6alt 2-n-Butyl-4-chloro-1-1(2'-(cyanomethyl)biphenyl-4-yl)methyl~-5-(metboxymethyl)imidazole (2.60 g) and a 1:1 mixture of concentrated aqueous HCl and glacial acetic acid (50 mL) were mixed together and then refluxed for 6 hour6. The 601vent6 were removed in vacuo and water (200 mL) wa6 added to the re6idue.
The pH was adju6ted to 3 with concentrated NH40H and this aqueous mixture was eYtracted with etbyl acetate (3 x 200 mL). The organic layers were combined, dried (MgS04) and the 601vent removed in vacuo to yield an oil. Subseguent flash chromatography in 60:40 ethyl 3 acetate/hexane to 100% isopropanol yielded 1.07 g of a glass. This product was dissolved in acetone and dicyclohexylamine was added (1 eq). A gum precipitated which was redi~olved with more acetone (total of 75 mL) and heat. Upon cooling, 601id precipitate was obtained (291 mg); m.p. 135.0-137Ø
NMR ~hows -OCH3 to be mis~ing. NMR (200 MHz, CDC13) ~ 7.43-7.13 (m, 6H); 6.95 (d, 2H, J. 8Hz);
5.20 (6, 2H) 4.46 (6, 2H); 3.45 (6, 2H); 2.76 (m, 2H);
2.60 (t, 2H, J= 7Hz); 2.00-1.03 (m, 24H); 0.87 (t, 3H, J= 7Hz). Mas6 Calcd. for C23H25ClN203:
412 1554. ~ound: 412.1544.
~xample 176 PART A: Preparation of 2-n-Butyl-4-chloro-1-t(2~-(hydrazido)biphenyl-4-yl)met~yl]-5-(methoxy-lS methYl)imidazole 2-~-Butyl-1-~(2'-carbomethoxybiphenyl-4-yl)-methyl]-4-chloro-5-(methoxymet~yl)imidazole (2.00 g, 4.7 mmol, 1 eq), hydrazine (1.5 mL, 46.8 mmol, 10 eq) and methanol (30 mL) were mixed together and then refluxed for 3 days after which 1.5 mL more of hydrazine was added and the reaction refluxed for another day. More hydrazine (1.5 mL) wa6 again added and the reaction was refluxed for an additional day.
The reaction wa6 worked up by fir6t removing the hydrazine and methanol in vacuo, following by taking up the residue in ethyl acetate (200 mL) and wa6hing it with water (3 x 100 mL). The organic layer wa6 dried (MgS04) and the 601vent removed in vacuo to yield 1.37 g of a white gla66. NMR (CDC13, 200 MHz,) ~ 7.67-7.31 (m, 4H); 7.40 (d, 2H, JS 9Hz):
7.03 (d, 2H, J= 9Hz); 7.56 (b6, lH): 5.17 (6, 2H):
4.27 (~, 2H); 3.25 (~, 3H); 2.57 (t, 2H, J= 7Hz); 1.70 (t of t, 2H, 7,7Hz); 1.34 (t of q, 2H), J= 7,7Hz);
0.86 (t, 3H, J= 7Hz). Anal. Calcd. for C23H27ClN402:
1 3340~2 C, 64.70; H, 6.37; N, 13.12. Found: C, 64.47; H, 6.35; N, 12.85.
PART B: Preparation of 2-n-Butyl-4-chloro-5-methoxy-methyl-l-t4-(2-(trifluoromethyl6ulfonylhydra-zido~biPhenyl-4-yl)methyllimidazole A ~olution of triflic anhydride (0.42 mL, 2.5 mmol, 1.5 eq) in methylene chloride (2 mL) was slowly dripped into a ~tirred ~olution at -78C of 2-n-butyl-4-chloro-1-t(2'-(hydrazido)biphenyl-4-yl)methyl]-5-(methoxymethyl)imidazole (0.71 g, 1.7 mmol, 1.0 eq) and triethylamine (0.35 mL, 2.5 mmol, 1.5 eq) in methylene chloride (5 mL). The 601ution wa~ 6tirred at -78C for 1 ~our and the~ allowed to warm to room temperature. After 2 hour6 at room temperature, water (100 mL) was added, the pH adju~ted to 5 and the aqueou~ layer extracted with ethyl acetate (3 x 100 mL). The organic layerE were dried (MgS04), the 601vent removed in vacuo, and the residue fla~h chromatographed over 6ilica gel beginning in 1:1 hexane/ethyl acetate and fini6hing in 100% ethyl acetate to yield 380 mg of a light yellow gla~6. NMR
(200 MHz, CDC13) ~ 7.82-7.15 (m, 8H): 6.94 (d, 2H, J= 8Hz): 5.13 (s, 2H): 4.25 (~, 2H): 3.17 (~, 3H):
2.53 (t, 2H, J= 7Hz): 1.69 (t of t, 2H, J= 7,7Hz):
1.27 (t of q, 2H, J= 7,7Hz): 0.81 (t, 3H, J= 7Hz).
Fast Atom Bombardment MaE~ Spectrum: Ma~ Calcd. for C24H26ClF3N4045: 559.15. Found: 559.12.
Example 177 PART A: Preparation of 4'-Methylbiphenyl-2-carboxalde-hyde Methyl 4~-methylbiphenyl-2-carboxylate (20.00 g, 88 mmol, 1 eq) was di6601ved in dry toluene (250 mL) 1 3340~2 and cooled to -78: Diisobutylaluminum hydride (1.0 M
in toluene, 220.0 mL, 220 mmol, 2.2 eq) wa6 then dripped in 610wly over 25 minute6 keeping the temperature under -70. When the addition was complete, the mixture waE 6tirred at -78 for 15 minutes and then methanol (10 mL) wa6 added cautiously. ~en ga6 evolution was complete, the mixture was poured into a 601ution of Rochelle 6alt (100 mL of saturated solution plus 600 mL water). The mixture was stirred or 6ha~en until an extractable solution was obtained. The layer6 were 6eparated and the aqueous layer extracted with ether (2 x 200 mL).
The organic layers were combined, dried (MgSO4) and the solvent removed in vacuo to yield 16.7 q of a light yellow oil. NMR (200 MHz, CDC13) ~
7.56-7.16 (m, 8H); 4.59 (s, 2H); 2.40 (s, 3H); 1.74 (6, lH). This oil (16.7 g, 84 mmol, 1 eg) was 6ubsequently oxidized by di6solving in methylene chloride (100 mL) and stirring with manganese dioxide (7 34 g~ 84 mmol, 1 eq). After 6tirring for one day at room temperature, more manganese dioxide (14.68 g, 168 mmol, 2 eq) was added. The next day, 14.68 g more of manganese dioxide was again added. After another day of stirring, the reaction was filtered through Celite~ and the filtrate evaporated to an oil. The oil was chromatographed in 9:1 hexane/ethyl acetate over silica gel to yield 13.4 g of a light yellow opaque oil. The above oxidation can also be performed using pyridinium chlorochromate. NMR (CDC13, 200 MHz) ~ 9.98 (s, lH); 8.01 (d, lH, J= 7Hz); 7.64 (t, lH, J= 7Hz); 7.53-7.38 (m, 2H); 7.28-7.17 (m, 4H);
2.43 (s, 3H). Mass Calcd. for C14H120: 196.0888.
Found: 196.0881.
200 ~ 3340~2 PART B: Preparation of 4~-Methyl-2-(2-nitroethen Yl)biphenyl 4'-Methylbiphenyl-2-carboxaldehyde (13.~1 g, 67.3 mmol (1.0 eq), nitromethane (4.74 mL, 87.5 mmol, 1.3 eq), ammonium acetate (2.07 g, 26.0 mmol, 0.4 eq) and glacial acetic acid (30 mL) were mixed and refluxed for 2 day6, at which time more nitromethane (4.74 mL) and ammonium acetate (2.07 g) were added and the reaction was refluxed for an additional 5 hours.
The reaction mixture was poured into ice water (300 mL) and extracted with ethyl acetate (300 mL). The ethyl acetate layer was wa6hed with water (3 x 200 mL), the organic layer dried (~gS04), the 601vent removed iD vacuo and the re~idue chromatographed in 1:1 hexane/toluene to yield 11.22 g of a light yellow oil which cry6tallized. The product was recry6tallized from methylcyclohexane to yield 8.47 g of yellow cry6tals: m.p. 64.0-65Ø NMR (200 MHz, CDC13) ~ 8.04 (d, lH, J= 13Hz): 7.69 (d, lH, J=
9Hz) 7.59-7.37 (m, 4H): 7.50 (d, lH, Jz 13 Hz): 7.27 (d, 2H, J= 7Hz): 7.19 (d, 2H, J= 7Hz): 2.41 (6, 3H).
Anal. Calcd. for C15H13N02: C, 75.30: H, 5.48;
N, 5.85. Found: C, 75.32: H, 5.56: N, 5.5B.
PART C: Preparation of 4'-methyl-2-(1,2,3-triazol-4-yl)biPhenyl 4'-Methyl-2-(2-nitroethen-1-yl)biphenyl (6.58 g, 27.5 mmol, 1 eg), 60dium azide (5.40 g, 82.3 mmol, 3 eq), and dimethyl6ulfoxide (minimum to di~601ve everything) were mixed together and ~tirred at room temperature for 4.5 hours. Ethyl acetate (500 mL) was then added and the organic phase washed with water (3 x 400 mL). T~e organic layer wa~ dried (MgS04) and the solvent removed in vacuo to yield 6.54 g of an 201 1 3340~2 orange glass. Chromatography in 75:25 hexane~ethyl acetate yielded 2.87 g of of a yellow glass. NMR (200 MHz, CDC13) ~ 7.83 (m, lH); 7.51-7.32 (m, 3H);
7.18 (d, 2H, J= BHz); 7.13 (d, 2H, J= 8Hz): 7.03 (s, lH); 2.38 (~, 3H). Mass Calcd. for C15H13N3:
235.1110. Found: 235.1111.
PART D: Preparation of 4'-Methyl-2-(N-(trip~enyl-methyl)-1~2~3-triazol-4-yl)biphenYl 4'-Methyl-2-(1,2,3-triazol-4-yl)biphenyl (2.61 g, 11 mmol, 1.0 eq), triethylamine (1.69 mL, 12 mmol, 1 eq), tritylbromide ~3.88 g, 12 mmol, 1 eq) and methylene chloride (30 mL) were mixed and ~tirred at 0C and then allowed to warm to room temperature.
After 1 hour, ethyl acetate was added (200 mL) and the organic phase was washed with water (3 x 200 mL). The organic layer was dried (MgS04) and the solvent removed in vacuo to yield S.lS g of a yellow ~olid.
This product was recrystallized from methylcyclohexane to give 3.26 9 of off-white crystal~; m.p.
181.0-182.5. NMR (200 MHz, CDC13) ~ 8.18 (d, lH, J= 7Hz): 7.50-7.16 (m, 12H); 7.05-6.89 (m, 10 Hz);
6.47 (6 , lH); 2.54 (~, 3H). Anal. Calcd. for C34H27N3: C, 85.50; H, 5.70; N, 8.80. Found:
C, 86.60; H, 5.80; N, 8.94.
PART E: Preparation of 2-n-Butyl-4-chloro-5-hydroxymethyl-l-[(2'-(N-(triphenylmethyl)-1,2,3-triazol-4-yl)biphenyl-4-yl)methyl~-imidazole 4'-Methyl-2-(N-(triphenylmethyl)-1,2,3-triazol-4-yl)biphenyl (3.14 g, 6.57 mmole6) was brominated in the benzylic position by the procedure in Example 85, Part B, using benzoylperoxide in~tead of AIBN as radical initiator. Filtration of succinimide and evaporation yielded 4.45 g of a crude oil which was used as is.
NMR (200 MHz, CDC13) ~ CH2Br, 4.41. Thi6 bromide (4.33 g, approx. 7.8 mmol, 1 eq) wa6 alkylated onto 2-n-butyl-4-chloro-5-(hydroxymethyl)imidazole by the procedure de6cribed in ~xample 1, Part A. Fla6h chromatography in 75:Z5 hexane~ethyl acetate over 6ilica gel yielded a yellow 601id (0.67 g) which wa6 recry~tallized from carbon tetrachloride to yield 447 mg of white cry6tal6: m.p. 173.0-176.5. NMR
(CDC13, 200 MHz) ~ 8.03 (d, lH, J- 9Hz): 7.51-7.14 (m, 14H); 6.98 (m, 6H): 6.86 (d, 2H, J~ 9Hz): 6.63 (6, lH); 5.15 (6, 2H): 4.33 (6, 2H): 2.53 (t, 2H, J~ 7Hz):
1.15 (t of t, 2H, J= 7,7Hz): 1.32 (t of g, 2H, J5 7,7Hz): 0.87 (t, 3H, J= 7Hz). Ha66 Calcd. for C42H38ClN50: 663.2765. Pound: 663.2762.
PART P: Preparation of 2-n-Butyl-4-chloro-5-hydroxy-methyl-l-[(2'-1,2,3-triazol-4-yl)biphenyl-4-yl)methYl~imidazole 2-n-Butyl-4-chloro-5-hydroxymethyl-1-t(2'-(N-(triphenylmethyl)triazol-4-yl)biphenyl-4-yl)methyl]-imidazole (408 mq, 0.6 mmol, 1 eq), 1,4-dioxane (5 mL), water (1 mL) and 4.0 N HCl in dioxane (0.46 mL, 1.8 mmol, 3 eq) were mixed and ~tirred at room temperature. After 2 hours, water wa6 added (200 mL), and the aqueou6 layer extracted with ethyl acetate (3 x 200 mL). The organic layer6 were dried (MgS04) and the 601vent removed in vacuo to yield 260 mg of an off-white gla66. Pla6h chromatography of the product in 100% ethyl acetate over 6ilica gel yielded 140 mg of a white gla66. NMR (200 MHz, CDC13) ~ 7.82 (m, lH): 7.50-7.25 (m, 3H): 7.17 (d, 2H, J= 9Hz): 6.98 (d, 2H, J= 9HZ); 6.95 (6, lH); 5.23 (6, 2H): 4.52 t6. 2H):
2.58 (t, 2H, J= 7Hz): 1.63 (t of t, 2H, J- 7,7Hz):
1.30 (t of q, 2H, J= 7,7Hz): 0.82 (t, 3H, J= 7Hz).
Ma6s Calcd. for C23H24ClN50: 421.1669. Pound:
421.1670.
-ExamPles 178 and 179 PART A: Preparation of Ethyl 3-(4-methylphenyl)-3-oxo-2-(al 1Y1 ) PrOPanOate Ethyl 3-(4-met~ylphenyi)-3-oxopropanoate (prepared as de6cribed in W. Wierenga and H. I.
Skulnick, J. Orq. Chem. (1979), 44, 310) (63.66 g, 309 mmol, 1 eq) wa6 added to a fre6hly prepared 60dium ethoxide 601ution (Na, 7.43 g, 323 ~mol, 1.05 eg:
EtOH, 250 mL). The ethanol wa6 remoYed 1n ~acuo and the re6idue wa6 di6601ved in DMF (250 mL). Allyl bromide (29.3 mL, 338 mmol, 1.1 eq) followed by 60dium iodide (4.56 g, 304 mmol, 1 eq) vere then added and the content6 ~tirred overnight at room temperature.
The DMF wa6 removed in vacuo, water (250 mL) wa6 added and tbe aqueous layer extracted with ethyl acetate (3 x 200 mL). The organic layer6 were dried (MgSO4) and the 601vent removed in vacuo to yield 74.21 g of an amber oil. NMR (200 MHz, CDC13) ~ 7.81 (d, 2H, J= 10Hz): 7.30 (d, 2H, J= 10 Hz); 5.96-5.72 (m, lH):
2 5.21-5.00 (m, 2H): 4.41 (t, lH, J= 7Hz): 4.16 (q, 2H, J= 7Hz): 2.78 (t, 2H, J= 7Hz): 2.42 (8, 3H): 1.18 (t, 3H, J= 7Hz). Anal. Calcd. for C15H18O3: C, - 73.15: H, 7.37. Eound: C, 73.10: H, 7.38.
PART B: Preparation of 3-Carboethoxy-4-(4-methyl-phenyl)-4-(oxo~butanal Ethyl 3-(4-methylphenyl)-3-oxo-2-(allyl)-propanoate (74.21 g, 301 mmol, 1.0 eq), 06mium tetroxide (100 mg, cat.), 60dium metaperiodate (141.8 g, 663 mmol, 2.2 eq), etber (500 mL) and water (1 L) were mixed and 6tirred at room temperature.
After 24 hour6, an additional 110 mg of O6O4 wa6 added and after another 24 hour6, 200 mg more of 204 1 3340~2 O~O4 was added together with 60dium metaperiodate (190 g, 888 mmol, 3.0 eq). After 4 day6, the layer6 were 6eparated and the ether layer wa6hed with aqueou6 60dium bi6ulfite (1 Y 500 mL) followed by brine (1 x 300 mL). The ether layer wa6 dried (HgSO4) and the 601vent removed in vacuo to yield 64.99 g of a dark brown oil. Thi~ oil wa6 fla6h chromatographed over 6ilica gel in 4:1 hexane/ethyl acetate to yield 37.5 g of an amber oil. NMR (200 MHz, CDC13) ~ 9.79 (s, lH): 7.93 (d, 2H, J= 9Hz): 7.27 (d, 2H, J- 9Hz): 4.87 (t, lH, J= 7Hz): 4.13 (q, 2H, J= 7Hz): 3.37-3.08 (AB
multiplet, 2H): 2.40 (6, 3H); 1.14 (t, 3H, J= 7Hz).
Anal- Calcd- for C14H164 C~ 67-73; H~ 6-50-~ound: C, 67.53; H, 6.54.
PART C: Preparation of 3-Carboethoxy-2-(4-methyl-Phenyl)furan Ethyl 3-CarboethoYy-4-(4-methylphenyl)-4-(oxo)-butanal (10.00 g), trifluoroacetic anhydride (50 mL) and trifluoroacetic acid (2 drop6) were mixed and 6tirred at 0 over ice and allowed to warm to room temperature. After 3 hour6, more trifluoroacetic anhydride (50 mL) together with trifluoroacetic acid (2 drop6) were added at room temperature. The next day, the 601vent wa6 removed ~n vacuo and the re6idue partitioned between 1 N NaOH (200 mL) and ethyl acetate (200 mL). The layer6 were 6eparated and the orqanic layer wa6hed with 1 N NaOH (2 x 200 mL). The organic layer wa6 dried (HgSO4) and the 601vent removed in vacuo to yield a brown oil (9.95 g) which wa6 fla6h chromatographed in 99:1 hexane~ethyl acetate to yield 2.57 g of an off-white 601id; m.p.
79.0-80.5. NMR (200 MHz, CDC13) ~ 7.88 (d, 2H, J= 9Hz); 7.42 (d, lH, J= 2Hz); 7.26 (d, 2H, J= 9Hz);
-~ 20s 1 334092 6.83 (d, lH, J=2Hz): 4.34 (q, 2H, J= 7Hz); 2.40 (8, 3H); 1.34 (t, 3H, J= 7Hz). Anal. Calcd. for ClgH14O3: C, 73.03; H, 6.13. Found: C, 73.52;
H, 6.30.
PART D: Preparation of 2-n-Butyl-l-t4-(3-carboxyfuran-2-yl)benzyl~-4-chloro-5-(hydroxymethyl)-imidazole (isomer A) and 2-n-butyl-1-t4-(3-carboxyfuran-2-yl)benzyl]-5-chloro-4-(hydroxy-methyl~imidazole (i60mer B~
3-Carboethoxy-2-(4-methylphenyl)furàn was brominated, alkylated, and ~aponified by the procedures described in Example 85, Parts B, C, and E.
I60mer A, the faster eluting ~60mer, was recrystallized from acetonitrile; m.p. 158.5-160Ø
NMR (200 MHz, DMS0-d6) ~ 12.80 (bm, lH); 7.92 (d, 2H, J= 9H): 7.82 (d, lH, J= 2Hz); 7.17 (d, 2H, J5 9Hz); 6.84 (d, lH, J= 2Hz): 5.30 (s, 2H), 5.30 (m, lH); 4.34 (6, 2H); 2.47 (t, 2H, J= 7Hz); 1.47 (t of t, 2H, J = 7,7Hz); 1.24 (t of q, 2H, J= 7,7Hz); 0.74 (t, 3H, J = 7Hz). Anal. Calcd. for C20H21ClN2O4:
C, 61.78; H, 5.44; N, 9.12. Found: C, 61.66; H, 5.39; N, 9.09.
~somer B wa6 recrystallized from nitromethane/
acetonitrile; m.p. 118.5-120.5. NMR (200 ~Hz, DMS0-d6) ~ 12.89 (bm, lH); 7.92 (d, 2H, J= 9Hz);
7.82 (d, lH, J= 2Hz); 7.13 (d, 2H, J= 9Hz); 6.83 (d, lH, J= 2Hz); 5.23 (8, 2H); 4.93 (m, lH) 4.29 (d, 2H, J= 7Hz); 2.57 (t, 2H, J= 7Hz); 1.53 (t of t, 2H, J =
7,7Hz); 1.27 tt of q, 2H, J= 7,7Hz); 0.77 (t, 3H, J=
7Hz). Mass Calcd. f 20 21 2 4 Found: 388.1171.
Example 180 1 3 S 4 0 9 2 PART A: Preparation of l-t(2'-Carbomethoxybiphenyl-4-yl)methyl~-2-butyl-4-chloro-5-(2-metho~y-ethoxYmethoxymethyl~imidazole To a-solution of 7.50 mL of 1.6 M n-butyllithi-um/hexane in 50 mL of tetrahydrofuran at 0 was added dropwi6e 1.50 mL of t-butanol. To this 601ution was added 4.52 g of 1-lt2'-carbomethoYybiphenyl-4-yl)-methyl]-2-butyl-4-chloro-5-hydroxymethylimidazole 1 followed by 1.50 ml of 2-methoxyetho~ymethyl chloride. The re6ulting 601ution wa6 6tirred at 25 for 16 hours. The mixture was diluted with diethyl ether, washed with water and brine, dried over anhydrou6 60dium 6ulfate, filtered and concentrated.
Column chromatoqraphy afforded 3.50 g of l-t(2'-carbomethoxybiphenyl-4-yl)methyl~-2-butyl-4-chloro-5-(2-methoxyethoxymethoxymethyl)imidazole. M~R (200 ~Hz, CDC13) ~ 7.83 (d, lH); 7.52 (t, lH): 7.40 (t, lH), 7.28 (m, 3H): 7.00 (d, lH): 5.19 (6, 2H): 4.68 (6, 2H): 4.48 (6, 2H): 3.67 (m, 2H): 3.64 (6, 3H):
3.54 (m, 2H): 3.37 (6, 3H): 2.58 (t, 2H): 1.67 (quint., 2H): 1.34 (6ext., 2H): 0.88 (t, 3H).
PART B: Preparation of l-t(2'-Carboxybiphenyl-4-yl)-methyl~-2-butyl-4-chloro-5-(2-methoxy-ethoxymethoxymethyl)imidazole A 601ution of 3.15 g of 1-[(2'-carbomethoxy-biphenyl-4-yl)methyl]-2-butyl-4-chloro-5-(2-methoxy-ethoxymethoxymethyl)imidazole and 2.77 g of pota66ium methanethiolate in 125 mL of dimethylformamide was 6tirred at 125 for 4 hour6. After cooling the 601vent was removed in vacuo, and the re~idue was dissolved in water. The resulting aqueou6 601ution was wa~hed with diethyl ether, adjusted to pH 3 207 1 3340~2 employing 10~ hydrochloric acid, and extracted with methylene chloride. The combined organic layer6 were washed with brine, dried over anhydrou6 60dium 6ulfate, filtered, and concentrated. The crude product was recry6tallized from chlorobutane to afford 2.45 g of 1-~(2'-carboxybiphenyl-4-yl)methyl]-2-butyl-4-chloro-5-(2-methoxyethoYymethoxymethyl)-imidazole. NMR (200 HHz, CDC13) ~ 7.95 (d, lH):
7.57 (t, lH): 7.46 (t, lH): 7.38 (m, 3H): 7.05 (d, 2H): 5.22 (8, 2H): 4.64 (6, 2H) 4.48 (6, 2H): 3.58 (m, 4H): 3.40 (6, 3H): 2.54 (t, 2H): 1.60 (guint., 2H): 1.32 (6ext., 2H): 0.84 (t, 3H).
PART C: Preparation of l-t(2'-~ethoxyaminocarbonyl-biphenyl-4-yl)methyl~-2-butyl-4-chloro-5-(2-methoxyethoxYmethoxymethyl)imidazole A 601ution of 0.24 ml of oxalyl chloride in 5 mL
of chloroform wa6 added dropwi6e to a 601ution of 1 mL
of dimethylformamide in 4 mL of chloroform at -20.
After thi6 601ution had been 6tirred at -20 for 20 minutes, 0.2~ mL of N-methylmorpholine wa6 added followed by 1.21 g of 1-[(2'-carboxybiphenyl-4-yl)-methyl]-2-butyl-4-chloro-5-(2-methoxyethoxymethoxy-methyl)imidazole. After another 20 minute6 at -20, 0 55 ml of N-methylmorpholine and 1.35 mL of methoxylamine were added to the mixture. The reaction mixture wa6 warmed 610wly to 25, 6tirred at 25 for 4 hour6, and finally refluxed for 40 hour6. After cooling the mixture wa6 diluted with ethyl acetate.
The re6ulting 601ution wa6 wa6hed with 10~
hydrochloric acid, water, 10% 60dium bicarbonate 601ution and brine. Finally the 601ution wa6 dried over anhydrou6 60dium 6ulfate, filtered, and concentrated in vacuo. Column chromatography (elution: methanol/chloroform) furni6hed 0.21 g of l-t(2'-methoxyaminocarbonylbiphenyl-4-yl)methyl~-2-butyl-g-chloro-5-(2-methoxyethoxymethoxymethyl)-imidazole. NMR (200 MHz, CDC13) ~ 7.85 (6, lH):
7.63 (d, lH); 7.53-7.33 (m, 5H); 7.05 (d, 2H): 5.20 (6, 2H); 4.67 (6, 2H): 4.47 (6, 2H): 3.63 (m, 5H):
3.55 (m, 2H): 3.36 (6, 3H): 2.56 (t, 2H); 1.67 (m, 2H); 1.32 (m, 2H); 0.87 (t, 3~).
PART D: Preparation of l-t(2'-Methoxyaminocarbonyl-biphenyl-4-yl)methyl]-2-butyl-4-chloro-5-hydroxYmethylimidazole A 601ution of 0.20 g of 1-1(2'-methoxyaminocar-bonylbiphenyl-4-yl)methyll-2-butyl-4-chloro-5-(2-methoxyethoxymethoxymethyl)imidazole in 60 ml of 1.5 Maqueou~ tetrafluoroboric acid/acetonitrile wa6 stirred for 20 hour6 at 25. The reaction mixture wa6 poured into dilute 60dium bicarbonate 601ution, and the re6ulting mixture wa6 extracted with diethyl ether.
2 The combined organic pha6e6 were wa6hed with brine, dried over anhydrou6 60dium 6ulfate, filtered, and concentrated. Column chromatography (elution:
methanol/chloroform) provided 0.11 g of l-t(2~-methoxyaminocarbonylbiphenyl-4-yl)methyl]-2-butyl-4-chloro-5-hydroxymethylimidazole. NMR (200 MHz, CDC13) ~ 11.31 (br 6, lH): 7.48 (m, lH); 7.41-7.33 (m, 5H); 7.09 (d, 2H); 5.27 (br 6, 3H); 4.32 (d, 2H);
3.44 (6, 3H); 2.49 (t, 2H); 1.48 (guint., 2H); 1.25 (6ext., 2H); 0.80 (t, 3H).
The following compounds were prepared according to the procedure6 described in the above example.
-NMR (200 MHz, DMSO-d6) Exa~ple 181 ~ 11.29 (br s, lH), N__~Cl 7.48 (m, lH), 7.33 (m, ~ ~ \~ OH lOH), 7.09 (d, 2H), 5.27 (d, 2H), 4.67 (s, ~ Co~CH C H 2H), 4.31 (s, 2H), 2.47 ~ 2 6 5 (t, 2H), 1.46 (quint., ~ 2H), 1.21 (sext., 2H), - " ~' 0.76 (t, 3H).
Example 182 ~ 10.81 (br ~, lH), N ~ Cl 9.02 (br s, lH), 7.55-- ~N ~ 7.35 (m, 6H), 7.11 (d, 2H), 5.28 (br 6, 3H), ~CON~O~ 4.34 (d, 2H), 2.50 (t, ~ 2H), 1.49 (quint., 2H), 1.25 (sext., 2H), 0.78 (t, 3H).
Example 183 PART A: Preparation of l-t(2'-Aminobiphenyl-4-yl) methyl]-2-butyl-4-chloro-5-hydroxymethyl-imidazole This compound was prepared according to the procedure described in Example 141, Part A. From 3.30 q of 1-[(2'-nitrobiphenyl-4-yl)methyl]-2-butyl-4-chloro-5-hydroxymethylimidazole, 1.60 q of iron powder, 3.20 ml of acetic acid, and 160 mL of methanol there was obtained 2.05 9 of 1-[(2'-aminobiphenyl-4-210 1 33409~
yl)methyl1-2-butyl-4-chloro-5-hydroxymethylimidazole.
NMR (200 MHz, CDC13) ~ 7.45 (d, 2H) 7.23-7.08 (m, 4H); 6.89-6.77 (m, 2H): 5.27 (s, 2H); 4.55 (br 6, 2H):
2.62 (t, 2H); 1.69 (quint., 2H); 1.37 (6ext., 2H);
0.88 (t, 3H).
PART B: Preparation of l-t(2'-Aminobiphenyl-4-yl)-methyl]-2-butyl-4-chloro-5-(2-methoxy-ethoxymethoxYmethyl)imidazole Thi6 compound was prepared according to the procedure described in Example 180, Part A. From 2.03 g of l-t(2~-aminobiphenyl-4-yl)methyl~-2-butyl-4-chloro-5-hydroxymethylimidazole, 3.75 mL of 1.6 M
n-butyllithium/hexane, 0.75 ml of t-butanol, 0.75 ml f 2-methoxyethoxymethyl chloride, and 25 ~L of tetrahydrofuran there was obtained 0.84 9 of 1-[(2~-aminobiphenyl-4-yl)methyl]-2-butyl-4-chloro-5-(2-methoxyethoxymethoxymethyl)imidazole. NMR (200 MHz, CDC13) ~ 7.42 (d, 2H); 7.19-7.03 (m, 4H);
6.86 (m, 2H); 5.20 (s, 2H); 4.69 (m, 2H); 4.49 (m, 2H); 3.67 (m, 2H), 3.54 (m, 2H); 3.37 (s, 3H); 2.59 (t, 2H); 1.67 (quint., 2H); 1.34 (sext., 2H); 0.87 (t, 3H).
PART C: Preparation of l-t(2'-Trifluoroacetamido-5biphenyl-4-yl)methyl]-2-butyl-4-chloro-5-(2-methoxYetboxymethoyymethyl)imidazole To a solution of 0.84 g of 1-t(2'-aminobiphenyl-4-yl)methyl]-2-butyl-4-chloro-5-(2-methoxyethoxy-methoxymethyl)imidazole, 0.23 g of 4-dimethylamino-pyridine, 1.28 mL of triethylamine, and 10 mL of tetrahydrofuran at 25 wa~ added dropwise 1.30 mL of trifluoroacetic an~ydride. The reaction mixture was stirred at 25 for 4 hours and then was poured into 211 1 3340~2 water. The resultinq 601ution was adju6ted to pH 4 using 10% hydrochloric acid and extracted with diethyl ether. The combined organic phase6 were wa6hed with water and brine, dried over anhydrou6 sodium culfate, filtered, and concentrated in vacuo. Column chromatography afforded 0.96 g of 1-t(2~-trifluoro-acetamidobiphenyl-4-yl)methyl]-2-butyl-4-chloro-5-(2-methoxyethoxymethoxymethyl)-imidazole. N~R (200 MHz, CDC13) ~ 8.22 (d, lH): 7.89 (br ~, lH): 7.44 (m, lH): 7.36-7.29 (m, 4H): 7.12 (d, 2H): 5.23 (6, 2H): 4.68 (8, 2H): 4.49 (s, 2H): 3.65 (m, 2H): 3.54 (m, 2H): 3.37 (s, 3H): 2.56 (t, 2H): 1.67 (quint., 2H): 1.34 (sext., 2H): 0.87 (t, 3H).
PART D: Preparation of l-t(2~-Trifluoroacetamido-biphenyl-4-yl)methyl]-2-butyl-4-chloro-5-hydroxYmethylimidazole Thi6 compound was prepared according to the procedure de6cribed in Example 180, Part D. From 0.96 g f 1-[(2~-trifluoroacetamidobiphenyl-4-yl)methyl-2-butyl-4-chloro-S-(2-methoxyethoxymethoxymethyl)-imidazole there was obtained 0.35 g of 1-t(2'-trifluoroacetamidobiphenyl-4-yl)methyl1-2-butyl-4-chloro-5-hydroxymethylimidazole. NMR (200 MHz, CDC13) ~ 8.24 (d, lH): 7.89 (br 6. lH): 7.46 (m, lH); 7.32 (m, 4H): 7.15 (d, 2H): 5.30 (s, 2H): 4.55 (d, 2H); 2.60 (t, 2H): 1.67 (br t, lH), 1.70 (quint., 2H); 1.36 (6ext., 2H); 0.88 (t, 3H).
-212 1 3340q 2 Example 184 PART A: Preparation of 2-(4-Methylphenoxy)-benzoic acid To a solution of 5.95 g of ~-cresol and 7.83 g of 2-chlorobenzoic in 50 mL of dimethylformamide at 25 was added, in portions, 14.50 g of anhydrou6 pota66ium carbonate. The re~ulting mixture wa6 heated to 80, and 0.10 g of copper(I) ~odide wa6 added. The reac-tion mixture then was refluxed for 16 hour6. While 6till hot the mixture was poured onto water-ice. The resultinq 6uspen6ion was filtered, and t~e filtrate vas adjusted to pH 3.0 using aqueous bydrochloric acid. The precipitate was recovered by filtration.
The crude 601id ~a~ dis~olved in an agueou6 sodium hydroxide 601ution. This 601ution was acidified to pH 6.0 u6ing hydrochloric acid, filtered, and then acidified to pH 3Ø Filtration provided 5.67 g of 2-(4-methylphenoxyl)benzoic acid which was employed in the following reaction without further purification.
NMR (200 MHz, CDCl ): ~ 8.15 (d of d, lH); 7.42 (d of d of d, lH); 7.23-7.12 (m, 3H); 6.97 (d, 2H);
6.80 (d, lH): 2.37 (6, 3H).
~ART B: Preparation of Methyl 2-(4-methylphenoxy)-benzoate A 601ution of 37.70 g of 2-(4-methylphenoxy)-benzoic acid was 12.0 mL of concentrated sulfuric acid in 500 mL of methanol was refluxed for 14 hours. After cooling, the reaction mixture wa6 concentrated in vacuo and the residue was added to a mixture of methylene chloride and water. The organic phase wa6 6eparated, washed with saturated 60dium bicarbonate solution and brine, dried over anhydrous sodium ~ulfate, filtered, and concentrated. The crude product was kugelrohr distilled (120-135/0.025 torr) to furnish 35.08 9 of l 3340q2 methyl 2-(4-methylphenoxyl)benzoate, m.p. 31-34. NMR
(200 MHz, CDC13) ~ 7.87 (d of d, lH); 7.39 (t of d, lH): 7.11 (m, 3H); 6.88 (m, 3H); 3.81 (6, 3H): 2.30 (6, 3H).
PART C: Preparation of Methyl 2-(4-bromomethyl-Phenoxy)benzoate A 601ution of 35.08 g of methyl 2-(4-methyl-phenoxy)benzoate, 25.7 g of N-bromo6uccinimide, 0.57 q of azobi6i60butyronitrile, and 1200 mL of carbon tetrachloride wa6 refluxed for 3 hour6. After cooling to room temperature the re6ulting 6u6pen6ion wa6 filtered and then concentrated in vacuo to provide 4.51 g of crude methyl 2-~4-bromomethylphenoxy)benz-oate which wa6 u6ed in a ~ub6eguent reaction without further purification; NMR (200 MHz, CDC13): ~
7.92 (d of d, lH): 7.45 (t of d, lH): 7.16 (m, 3H):
6.90 (m, 3H); 4.49 (6, 2H): 3.83 (6, 3H).
PART D: Preparation of 2-Butyl-4-chloro-1-t4-(2-carbomethoxyphenoxy)benzyl]-5-hydroxy-methYlimidazole To a 6u6pen6ion of 7.51 g of 60dium methoxide in100 mL of dimethylformamide at 25 wa6 added a solution of 26.50 g of 2-butyl-4(5)-chloro-5(4)-hydroxymethyl-imidazole in 100 mL of DHF. The re6ulting mixture wa6 6tirred at 25 for 0.25 hour6: to thi6 mixture wa6 added dropwi6e a 601ution of 45.1 g of methyl 2-(4-bromomethylphenoxy)benzoate in 100 mL of DMP.
~ inally, the reaction mixture wa6 6tirred at 40 for 4 hour6. After cooling to 25, the 601vent wa6 removed in vacuo. The re6idue wa6 di6601ved in ethyl acetate, and thi6 601ution wa6 wa6hed with water and brine, dried over anhydrou6 60dium 6ulfate, filtered, and concentrated. Column chromatography on 6ilica gel 1 3340~2 (elution:10-25~ ethyl acetate/benzene) afforded 7.80 g of 2-butyl-4-chloro-1-t4-(2-carbomethoxyphenoxy)-benzyl]-5-hydroxymethylimidazole. NMR (200 MHz, CDC13) ~ 7.92 (d, lH): 7.48 (t, lH): 7.21 (t, lH):
6.93 (m, 5H): 5.21 (6, 2H): 4.48 (6, 2H): 3.79 (6, 3H); 2.56 (t, 2H); 1.65 (~uint., 2H): 1.34 (6ext., 2H): 0.88 (t, 3H).
PART E: Preparation of 2-Butyl-4-chloro-1-t4-(2-carboxyphenoxy)benzyl~-5-hydroxymethyl-imidazole A solution of 7.70 q of 1-t4-(2-carbomethoxy-phenoxy)benzyl]-2-butyl-4-chloro-5-hydroxymethyl imidazole in 250 mL of ethanol and 125 ~L of 10~
aqueou6 60dium hydroxide was refluxed for 5 hour6.
After cooling, the reaction mixture wa6 filtered, and the 601vent was removed in vacuo. The re6idue wa6 di6solved in water, and the 601ution wa6 acidified to pH 3.5 u6ing hydrochloric acid. The precipitated 601id wa~ recovered by filtration and recry6tallized from acetone to furni6h 6.52 g of 2-butyl-4-chloro-1-[4-(2-carboxyphenoxy)benzyl~-5-hydroxymethylimidazole, m.p. 178-180. NMR (200 MHz, DMS0) ~ 7.79 (d, lH):
7.53 (t, lH): 7.23 (t, lH): 7.07 (d, 2H): 6.94 (d, lH): 6.87 (d, 2H): 5.18 (6, 2H): 4.32 (6, 2H); 2.47 (t, 2H): 1.46 (quint., 2H): 1.23 (6ext., 2H): 0.78 (t, 3H).
The following compound6 have been or could be prepared by the above procedure6.
Table 12 R 61 N~ R 8 No. R R R ~ _ MP(C) 185 n-butyl Cl CH20H4-S ~ 166-167 C~o2H
186 n-butyl Cl CH20H 4-N
Co2H
187 n-butyl Cl CH20H 4-N
188 n-propyl H CH20H 4-S
Co2H
189 n-propyl Cl CH20H 4-S
190 CH20CH2CH2CH2 Cl CH20H 4-S
C~
191 n-butyl Cl CH20H q-N
,CH2 -Example 192 PART A: Preparation of 1-(4-BenzyloxybenZyl)-2-bUtyl-4-chloro-S-hYdroxymethylimidazole To a 6u6pension of 1.43 g of sodium methoxide in 20 mL of dimethylformamide at 25 was added a solution of 5.00 g of 2-butyl-4(5)-chloro-5(4)-hydroxymethyl-imidazole in 15 mL of dimethylformamide lDMF). The re6ulting mixture wa6 stirred at 25 for 0.25 hour6, and then to this mixture wa6 added dropwi6e a 601ution f 4-benzyloxybenzyl chloride in 15 ~L of DMP.
Finally, the reaction mixture wa6 6tirred at 40, the 601vent wa6 removed in vacuo. The re6idue wa6 dissolved in ethyl acetate, and this solution was wa6hed wit~ water and brine, dried over anhydrou6 60dium sulfate, filtered, and concentrated. Column chromatography on silica gel (elution: 10-25~ ethyl acetate/benzene) afforded 3.27 g of 1-(4-benzyloxy-benzyl)-2-butyl-4-chloro-5-hydroxymethylimidazole:
m.p. 115-116: NMR (200 MHz, CDC13): ~ 7.39 (m, 5H); 6.94 (6, 4H): 5.15 (s, 2H): 5.04 (6, 2H): 4.47 (bs, 2H): 2.56 (t, 2H): 2.07 (bs, lH): 1.63 (quint., 2H): 1.32 (sext., 2H): 0.87 (t, 3H).
PART B: Preparation of 1-(4-Hydroxybenzyl)-2-butyl-4-chloro-5-hYdroxymethylimidazole A mixture of 0.50 g of 1-(4-benzyloxybenzyl)-2-butyl-4-chloro-5-hydroxy~ethylimidazole, 0.50 g of 10%
palladium/carbon and 40 mL of tetrahydrofuran was 6tirred at room temperature under hydrogen gas (1 atm.) for 6 hours. The mixture ~as filtered through Celite~ under nitrogen, and the re6ulting solution was concentrated in vacuo; The crude product was extracted with hot chloroform. After cooling, the chloroform mixture was concentrated in vacuo, and the resulting 601id was washed with hexane to afford 0.16 g of l-(4-hydroxybenzyl)-2-butyl-9-chloro-5-hydroxy-methylimidazole: NMR (200 MHz, DMS0-d6): ~ 9.43 (6, lH): 6.81 (A2B2, 4H): 5.21 (t, lH): 5.10 (6, 2H): 4.33 (d, 2H): 2.47 (t, 2H); 1.44 (quint 2H): 1.23 (6ext., 2H); 0.79 (t, 3H).
PART C: Preparation of l-t4-(2-Cyanobenzyloxy)benzyl]-2-butYl-4-chloro-5-~ydroyy~nethylimidazole To a 601ution of 1.00 g of 1-(4-hydroxybenzyl)-2-butyl-4-chloro-5-~ydroxymethylimidazole in 15 mL of DM~ at 25 wa6 added 0.185 g of ~odium methylate, and the re6ulting mixture wa6 6tirred at 25 for 0.25 hours. To thi6 mixture was then added a ~olution of 0.80 g of a-bromo-o-tolunitrile in 5 ~L of DM~. The reaction mixture wa6 6tirred at 25 for 16 hour6. The 601vent wa6 removed in vacuo, and the residue di6-601ved in ethyl acetate. Thi6 solution wa6 wa6hed with water and brine, dried over anhydrou6 60dium 6ulfate, filtered, and concentrated in vacuo. Column chromatography on silica gel (elution: 10-25% ethyl acetate/benzene) provided 0.76 g of 1-t4-(2-cyano-benzyloxy)benzyl]-2-butyl-4-chloro-5-hydroxymethyl-imidazole: NMR (200 HHz, CDC13): ~ 7.73-7.59 (m, 3H); 7.44 (m, lH): 6.96 (6, 4H); 5.23 (6, 2H): 5.14 (6, 2H): 4.50 (d, 2H): 2.57 (t, 2H): 1.66 (quint., 2H); 1.33 (6ext., 2H): 0.87 (t, 3H).
PART D: 1-t4-(2-Cyanobenzyloxy)benzyl~-2-butyl-4-chloro-5-cYanomethylimidazole To a 601ution of 0.?6 g of 1-t4-(2-cyanobenzyl-oxy)benzyl]-2-butyl-4-chloro-5-hydroxymethylimidazole in 20 mL of chloroform at 25 wa6 added dropwi6e 0.95 mL of thionyl chloride and the mixture wa6 6tirred at 25 for 2 hour6. The solvent wa6 removed in vacuo.
-218 ~ 334092 The residue wa6 di6solved in 20 mL of toluene, and then the toluene wa6 removed in vacuo. Finally, the residue was di6601ved in 10 mL of dimethyl 6ulfoxide, and the re6ulting 601ution wa6 added to a 601ution of 0.71 g of sodium cyanide in lO mL of dimethylsulfoxide.
The mixture wa6 6tirred at 25 for 1 hour and then poured into water. Thi6 emulsion wa~ extracted with ethyl acetate: and the combined organic pha6es were washed with water and brine, dried over anhydrou6 60dium 6ulfate, filtered, and concentrated. Column chromatography on 6ilica gel telution 0-25~ ethyl acetate/benzene) afforded 0.67 g of 1-t4-(2-cyano-benzyloxy)benzyl]-2-butyl-4-chloro-5-cyanomethyl-imidazole: NMR (200 MHz, CDC13): ~ 7.79-7.60 (m, 3H): 7.47 (m, lH): 7.00 (8, 4H): 5.24 (6, 2H): 5.14 (6, 2H); 3.46 (6, 2H): 2.66 (t, 2H): 1.71 (quint., 2H): 1.40 (6ext., 2H): 0.92 (t, 3H).
PART ~: l-t4-(2-Carboxybenzyloxy)benzyl]-2-butyl-4-chloroimidazole-5-acetic acid A 601ution of 0.65 g of 1-t4-(2-cyanobenzyloxy)-benzyl]-2-butyl-4-chloro-5-cyanomethylimidazole in 20 mL of ethylene glycol and 10 mL of 10% aqueous 60dium hydroxide wa6 refluxed for 14 hour~. After cooling, the reaction mixture was filtered, and the solvent wa6 removed in vacuo. The re~idue wa6 di6solved in water, and the 601ution wa6 acidified to pH 3.5 u6ing hydro-chloric acid. The precipitated 601id wa6 recovered by filtration and recry6tallized from aqueous ethanol to furnish 0.21 g of 1-14-(2-carboxybenzyloxy)benzyl~-2-butyl-4-chloroimidazole-5-acetic acid, m.p.
170-172: NMR (200 MHz, DMSO-d6): ~ 12.9 (b8, 2H):
7.94 (d, lH): 7.61 (d, lH): 7.60 (t, lH): 7.46 (t, lH): 6.99 (6, 4H): 5.45 (s, 2H); 5.11 (6, 2H): 3.49 (6, 2H): 2.52 (t, 2H); 1.48 (quint., 2H): 1.24 (6ext., 2H); 0.82 (t, 3H).
Example 193 PART A: Preparation of 1-(4-Hydroxybenzyl)-2-butyl-5-hYdroxymet~ylimidazole A mixture of 1.00 g of 10% palladium/carbon and 1.00 g of 1-(4-benzyloxybenzyl)-2-butyl-4-chloro-5-hydroxymethyl imidazole in 20 mL of methanol wa6 stirred at 25 for fi~e minutes. ~y~rogen ga6 wa6 bubbled into the 601ution, and t~e mixture was 6tirred under hydrogen ga6 (1 atm.) at 25 for 2 ~our6. The mixture wa6 filtered, and the resulting 601ution concentrated in vacuo to furni6h 0.75 g of 1-(4-hydroxybenzyl)-2-butyl-5-hydroxymethylimidazole: NMR
(200 MHz, DMSO-d6): ~ 9.75 (b6, lH); 7.55 (6, lH):
6.91 (A2B2, 4H): 5.80 (b6, lH): 5.35 (6, 2H): 4.45 (6, 2H): 2.89 (t, 2H): 1.44 (quint, 2H): 1.21 (6ext., 2H): 0.80 (t, 3H).
PART B: Preparation of l-t4-(2-CarboxybenzyloYy)-benzYl~-2-butYl-s-hydroxymethylimidazole The title compound wa6 prepared from 1-(4-hydroxybenzyl)-2-butyl-5-hydroxymethylimidazole u6ing the alkylation and hydroly6i6 procedures described in Example 192, Part~ C and E, m.p. 115-116 NMR (200 MHz, DMSO-d6): ~ 7.92 (d, lH): 7.59 (m, 2H): 7.43 (m, lH): 6.95 (A2B2, 4H): 6.74 (6, lH): 5.40 (6, 2H): 5.11 (~, 2H): 4.31 (6, 2H): 2.48 (t, 2H): 1.47 (quint., 2H): 1.23 (6ext., 2H): 0.77 (t, ~H).
ExamPle 194 PART A: Preparation of l-t4-(2-Cyanobenzyloxy)benzyl]-2-butYl-4-chloro-5-methoxymethylimidazole To a 601ution of 0.29 g of 1-t4-(2-cyanobenzyl-oxy)benzyl]-2-butyl-4-chloro-5-hydroxymet~ylimidazole in 8.0 mL of dimethyl 6ulfoxide at 25 wa6 added 0.93 g of potas~ium t-butoxide followed by 0.060 mL of 1 3340q2 methyl iodide. The reaction mixture was stirred at 25 for 2.5 hours and then was poured into water. The aqueous emulsion was extracted with ethyl acetate; the organic phases were combined and washed with water and brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. Column chromatography on silica gel (elution: 5-25~ ethyl acetate~benzene) furnished 0.17 g of 1-t4-(2-cyanobenzyloxy)benzyl]-2-butyl-4-chloro-5-methoxymethylimidazole: NMR (200 MHz, CDC13): ~ 7.72-7.57 (m, 3H); 7.43 (m, lH); 6.94 (s, 4H); 5.22 (s, 2H); 5.04 (s, 2H); 4.27 (s, 2H); 3.26 (8, 3H); 2.56 (t, 2H); 1.65 (quint., 2H); 1.33 (sext., 2H); 0.88 (t, 3H).
5 PART B: Preparation of 1-~4-(2-Carboxybenzyloxy)-benzyl]-2-butyl-4-chloro-5-methoxymethyl-imidazole The title compound was prepared from 1-[4-(2-cyanobenzyloxy)benzyl]-2-butyl-4-chloro-5-methoxy-methylimidazole via the hydrolysis procedure describedin Example 192, Part E; NMR (200 MHz, DMSO-d6):
7.91 (d, lH); 7.57 (m, 2H); 7.42 (m, lH); 6.97 (A2B2, 4H); 5.41 (s, 2H): 5.09 (s, 2H); 4.27 (3, 2H); 3.17 (s, 3H); 2.49 (t, 2H); 1.44 (quint, 2H);
1.21 (sext., 2H); 0.79 (t, 3H).
The compounds shown in Table 13 where X =
-OCH2- were prepared or could be prepared employing the above procedures of Examples 192-194 and procedures previously described.
221 1 3~4092 Table 13 N--~
'R6~N ~iR8 Ex 6 R7 R8 ~R13 MP ( C ) 195 n-butyl Cl CH20H 4-ocH2~3 (oil )a 196 n-butyl Cl CH20H 3-ocH2~3 19 7 n - bu t y 1 C 1 CH2 OCH2 CH 3 4 - OCH
198 n-butyl Cl CH20CH2C6HC 4-OCH
C~H
199 n-butyl Cl CH20CCH3 4-OCH2~ ~oil)b 3 2 2 2 g - OCH
201 n-propyl CF3 CH20H 4~ H
1 3340q2 a NMR (200 MHz, DMS0-d6): ~ 7.91 (d, lH):
7.58 (m, 2H); 7.42 (m, lH) 6.98 (A2B2, 4H): 5.42 (s, 2H); 5.15 (s, 2H): 4.32 (s, 2H): 2.48 (t, 2H): 1.44 (quint., 2H): 1.23 (6ext., 2H): 0.79 (t, 3H).
b NMR (200 MHz, CDC13): ~ 8.13 (d, lH):
7.75 (d, lH): 7.58 (t, lH) 7.39 (t, lH) 6-88 (A2B2, 4H): 5.51 (s, 2H): 5.04 (s, 2H): 4.95 (s, 2H): 2.60 (t, 2H): 1.83 (fi, 3H): 1.65 (quint., 2H): 1.32 (sext., 2H) 0.85 (t, 3H).
ExamPle 202 PART A: MethYl 2-[4-(BromomethYl)benzoyllbenzoate Methyl 2-toluylbenzoate (CA reg. # 6424-25-5:
available by simple e6terification of commercially available 2-toluylbenzoic acid) (10.00 g, 39.3 mmol, 1 eq), N-bromosuccinimide (7.00 g, 39.3 mmol, 1 eq), benzoyl peroxide (1.0 g) and 100 mL carbon tetra-chloride were mixed and refluxed overnight (peroxide added last). The mixture was filtered and 250 mL of a 100 g/l aqueous solution of ~odium bisulfite solution was added. The layers were separated and the organic layer was dried (MgS04) and concentrated. The brown solid residue was recrystallized from ether/hexane to give 6.47 g of product; m.p. 88.2-91.5. NMR (200 MHz, CDC13) ~ 8.07 (d, lH, J= 7Hz): 7.82-7.07 (m, 7H): 4.50 (s, 2H): 3.67 (s, 3H). Anal. Calcd. for C16H13O3Br:
C, 57.68: H, 3.93: Br, 23.98. Pound: C, 57.84: H, 4.04: Br 23.99. Mass Calcd. for C16H13O3Br:
332.0048. Found: 332.0033.
1 3}409~
PART B: Preparation of 2-Butyl-1-~4-(2-carbomethoxy-benzoyl)benzyl]-4-chloro-5-hydroxymethyl-imidazole To a 601ution of 2-butyl-4-chloro-5-(hydroxy-methyl)imidazole (11.12 g, 54 mmol, 1 eq) in 200 mL
methanol was added dropwi~e a fre6hly prepared 60dium methoxide 601ution (1.36 g Na, 59 mmol, 1.1 eg in 50 mL MeOH). After 6tirring for O.S ~our6, the methanol was removed in vacuo and the re6ultant gla66 wa6 dis601ved in 200 mL DMF. To thi6 mixture wa6 added a 601ution of methyl 2-t4-(bromomethyl)benzoyl]benzoate (18.00 g, 59 mmol, 1.1 eg) in DM~ and the entire content6 wa~ 6tirred overnight under N2 at room temperature. The 601vent wa6 then removed in ~acuo and the re~idue dis601ved in 500 mL ethyl acetate and 500 mL H20. The layer6 were 6eparated and the aqueous layer wa~ extracted twice with 500 mL portion6 of ethyl acetate. The organic layer~ were dried and concentrated and the crude product fla6h chroma-tographed to ~eparate the two regioi60mer~ in 60:40hexane/ethyl acetate over 6ilica gel. The fa6ter moving i60mer was i601ated to yield 14.72 g of a gla~y 601id. NMR (200 MHz, CDC13) ~ 8.03 (d, lH, J=
7Hz): 7.67 (m, 4H): 7.36 (d, lH, J= 7Hz): 7.05 (d, 2H, J= 7Hz); 5.28 (6, 2H): 4.43 (6. 2H): 3.63 (6, 3H):
2.53 (t, 2H, J= 7Hz): 1.60 (t of t, 2H, J= 7,7Hz):
1.30 (t of q, 2H, J= 7,7Hz): 0.87 (t, 3H, J= 7Hz).
' 25 26 3 4 5 Found: 586.1285.
1 3~4092 PART C: 2-Butyl-l-t4-(2-Carboxybenzoyl)benzyl~-4-chloro-5-(hYdroxymethyl)imidazole 2-Butyl-l-t4-(2-carbomethoxybenzoyl)benzyl~-4-chloro-5-hydroxymethylimidazole (500 mg, 1.13 mmol, 1 eq), 0.5 N KOH in methanol (2.27 mL, 1.14 mmol, 1 eq), and O.S mL of H2O were mixed and stirred.
After 6 hours, water (50 mL) was added and the pH was lowered to 3-5 with conc. HCl. The agueous mixture wa6 extracted with ethyl acetate (3 x SO mL) and the organic layers were dried (HgSO4) and concentrated to gi~e 200 mg of product: m.p. 90.0-95Ø NMR (200 MHz, CDC13) ~ 8.05 (d, lH, J. 7Hz); 7.48-7.75 (m, 4H); 7.37 (d, lH, J= 7Hz); 7.00 (d, 2H, J= 7Hz); 5.20 (6, 2H); 4.40 (6, 2H); 2.45 (t, 2H, J~ 7Hz); 1.50 (t f t, 2H, J= 7Hz); 1.25 (t of g, 2H, J= 7Hz): 0.79 (t, 3H, J= 7Hz). Anal. Calcd. for C23H23ClN2O4-(CH30H): C, 62.81: H, 5.93: ~ound: C, 62.95: H, S.99. Mass spec-trum shows M-H2O. Mass Calcd. for C23H23ClN2O4-H2O:
408,1235. Found: 408.1228.
ExamPle 203 Preparation of 2-n-Butyl-1-~4-(2-carboxybenzoyl)-benzyl-4-hydroxymethyl-5-chlorimidazole Using the procedure of Example 202, 2-n-butyl-1-t4-(2-carboxybenzoyl)benzyl]-4-hydroxymethyl-S-chloro-imidazole was prepared from 2-n-butyl-1-t4-(2-carbo-methoxybenzoyl)benzyl]-4-hydroxymethyl-S-chloro-imidazole, m.p. 214.0-216Ø NMR (200 MHz, CDC1 DMSO-d6) ~ 8.07 (d, lH, J. 7,7Hz): 7.32 (d, lH, J=
7Hz): 7.10 (d, 2H, J= 7Hz): S.l9 (s, 2H) 4.50 (s, 2H): 2.61 (t, 2H, J= 7Hz): 1.63 (t of t, 2H, J~
7,7Hz); 1.33 (t of q, 2H, J= 7,7Hz): 0.87 (t, 3H, J=
7Hz). Titration of the product with 1.000 N NaOH
showed the presence of exactly one acidic functionality. Anal. Calcd. for C23H23ClN2O4:
1 3340~2 C, 64.71; H, 5.43; N, 6.56. Pound: C, 64.75; H, 5.30; N, 6.65.
Example 205 PART A: Preparation of 2-Butyl-l-t4-(2-carbomethoxy-benzoyl)benzyl]-4-chloro-5-(chloromethyl)-imidazole, hYdrochloride 6alt 2-Butyl-1-~4-(2-carbomethoxybenzoyl)benzyl~-4-chloro-5-hydroxymethylimidazole (5.00 g, 11.3 ~ol, 1 1 eq) wa~ di6~01ved in 50 mL chloroform and to t~i6 solution wa6 dropwi6e added thionyl chloride (4.13 mL, 56.6 mmol, S eq) with 6tirring at room temperature.
After 4 hour6, the 601vent and exce66 thionyl chloride were removed by rotary evaporation. Toluene (100 mL) wa6 added to the recidue and the ~olvent again removed by rotary evaporation. Toluene wa6 again added and while evaporating the second time, product cry6tallized from 601ution yielding 2.91 g of a white ~olid: m.p.
139.0-143.5. NMR (200 MHz, CDC13) ~ 8.07 (d, lH, J= 7Hz): 7.~0 (d, 2H, J= lOHz): 7.68 (t, lH, J= 7Hz):
7.58 (t, lH, J= 7Hz): 7.35 (d, lH, J= 7Hz); 7.13 (d, 2H, J= lOHz): 5.43 (~, 2H): 4.42 (6, 2H): 3.67 (6, 3H): 2.96 (m, 2H): 1.75 (m, 2H): 1.39 (m, 2H): 0.88 (t, 2H, J= 7Hz). Mas6 Calcd. for C24H24C12N203:
458.1162. ~ound: 458.1160.
PART B: 2-Butyl-1-[4-(2-Carbomethoxybenzoyl)-benzy~]-4-chloro-5-((1,2,4-triazol-1-yl)-methYl~imidazole 2-Butyl-l-t4-(2-carbomethoxybenzoyl)benzyl]-4-chloro-5-chloromethylimidazole-HCl ~alt (1.00 g, 2.06 mmol, 1.0 eq), pota66ium triazolide (0.26 g, 2.39 mmol, 1.1 eq) and DM~ (50 mL) were mixed and heated at 90 under N2 overnight. The reaction was wor~ed up by removing the solvent in vacuo, taking up the residue in water (200 mL) and ethyl acetate (200 mL), 6epa-rating the layers and extracting the aqueou6 with ethyl acetate (2 x 200 mL). The organic layer~ were dried (MgSO4) and concentrated; the re~idue wa6 fla~h chromatographed over silica gel in 100% ethyl acetate to give 780 mq of a white gla6~y ~olid. NMR
(200 MHz, CDC13) ~ 8.05 (~, lH): 8.05 (d, lH, J= 7Hz):
7.83 (~, lH); 7.74 (d, 2H, J= lOHz); 7.66 (t, lH, J=
7Hz); 7.58 (t. lH, J= 7Hz); 7.33 (d, lH, J= 7Hz); 6.98 (d, 2H, J= 7Hz); 5.37 (6, 2H); 5.15 t~, 2H); 3.69 (~, 3H); 2.56 (t, 2H, J= 7Hz); 1.73 (m, 2H); 1.36 ( t of q, 2H, J= 7,7Hz); 0.87 (t, 3H, J 7Hz). Ma~ Calcd.
for C26H26ClN5O3: 491.1722. ~ound: 491.1816.
The following intermediate~ were prepared by the above procedure u~ing the appropriate nucleophile, imidazole ~tarting material, and ~olvent.
-N ~
R6~N ~R8 S ~
l O
~ `CR
R6 R R _ ~P(C) n-butyl Cl CH2-N ~ N ~ (oil) ~ 2 3 D-butyl Cl CH2N3 ~ 127.0-129.5 n-butyl Cl CH2CN ~ (oil) n-butyl Cl CH20CH3 ~ (601id) a NMR (200 MHz, CDC13) ~ 8.05 (d, lH, J=
7Hz): 7.72 (d, 2H, J= 8Hz); 7.65 (t, lH, J=
7Hz); 7.56 (t, lH, J= 7Hz); 7.36 (d, lH, J~
7Hz): 7.33 (b6, lH): 7.00 (b6, lH): 6.89 (d, 25 2H, J= 8Hz); 6.78 (bs, lH); 4.91 (6, 2H);
4.88 (6, 2H); 3.67 (~, 3H); 2.54 (t, 2H, J=
7Hz); 1.65 (t of t, 2H, J= 7,7Hz); 1.33 (t of q, 2H, J= 7,7Hz); 0.85 (t, 3H, J= 7Hz).
b NMR (200 MHz, CDC13) ~ 8.05 (d, lH, J=
30 7Hz); 7.76 (d, 2H, J= lOHz); 7.64 (t, lH, J=
7Hz); 7.56 (t, lH, J= 7Hz); 7.36 (d, lH, J=
7Hz): 7.06 (d, 2H, J= lOHz); 5.24 (~, 2H);
3.66 (~, 3H); 3.47 (6, 2H); 2.63 (t, 2H, J=
7Hz); 1.70 (t of t, 2H, J= 7,7Hz); 1.37 (t of 35 q, 2H, J= 7,7Hz); 0.89 (t, 3H, J= 7Hz).
- 1 334~2 c NMR (200 MHz, CDC13) ~ 8.05 (d, lH, J=
8Hz); 7.72 (d, 2H, J= 8Hz); 7.61 (m, 2H);
7.38 (d, lH, J= 7Hz); 7.04 (d, 2H, J= 7Hz);
5.20 (6, 2H); 4.26 (6, 2H); 3.63 (6, 3H);
3.21 (6, 3H); 2.50 (t, 2H, J= 7Hz); 1.65 (m, 2H); 1.29 (m, 2H): 0.84 (t, 3H, J= 7Hz).
PART C: 2-Butyl-l-t4-(2-Carboxybenzoyl)benzyl]-4-c~loro-5-((1~2~4-triazol-l-Yl)methyl)imidazole 102-Butyl-l-t4-(2-carbomethoxybenzoyl)benzyl]-4-c~loro-5-((1,2,4-triazol-1-yl)met~yl)imidazole (780 mg, 1.59 mmol, 1 eq), 0.5 N ~OH in MeOH (6.34 mL, 3.17 mmol, 2 eq) and methanol (20 mL) were mixed and 6tirred at 20 under N2. After 2.5 ~our6, one more equivalent of O.S N KOH in ~eOH wa6 added. After 6even hour6, the 601ution wa6 acidified to a pH of 4 with 1 N HCl, and 200 mL each of et~yl acetate and water wa6 added. The layer6 were 6eparated and the aqueou6 layer wa6 extracted with ethyl acetate (2 x 200 mL). T~e organic layer6 were dried (MgSO4) and concentrated to give 640 mg of a white gla66y 6clid:
m.p. 180.0-188Ø NMR (200 MHz, CDC13) ~ 7.94 (d, lH, J= 7Hz); 7.74 (6, lH): 7.65 (6, lH); 7.55 (d, 2H, J= 7Hz): 7.70-7.50 (m, 3H); 6.67 (d, 2H, J= 7Hz); 5.34 (6, 2H): 5.14 (6, 2H); 2.64 (t, 2H, J= 7Hz); 1.74 (t of t, 2H, J= 7,7Hz): 1.36 (t of q, 2H, J= 7,7Hz); 0.89 (t, 3H, J= 7Hz). Anal. Calcd. for C25H24ClN5O3-EtOAc:
C, 61.53; H, 5.70; N, 12.37. Found: C, 61.72; H, 5.19, N, 12.27.
Example6 205-207 in Table 14 were prepared by t~e procedure de6cribed in Example 203, Part C u6ing t~e appropriate imidazole 6tarting material6.
Table 14 1 334092 N ~
R6 ~ N ~ R8 ~3~o ~
No. R6 R R R13 MP(C) 205 n-butyl Cl CH2-N ~ CO2H (oil)a 206 n-butyl Cl CH2~3 C02H 188.0-190.0 207 n-butyl Cl CH20CH3 C02H 210.0-211.5 a NMR (200 ~Hz, CDC13/D20 exchange) ~
9.67 (~, lH); 7.98 (d, lH, J= 7Hz); 7.63 (t, lH, J= 7Hz); 7.55 (t, 2H, J= 7Hz); 7.41 (d, 2H, J= lOHz); 7.41 (d, lH, J= 7Hz); 7.09 (8, lH); 7.08 (6, lH); 6.70 (d, 2H, J= lOHz);
5.65 (~, 2H); 5.58 (~, 2H); 2.59 (t, 2H, J= 7Hz); 1.71 (t of t, 2H, J= 7,7Hz); 1.36 (t of q, 2H, J= 7,7Hz); 0.87 (t, 3H, J= 7Hz).
ExamPle 208 PART A: Preparation of 2-Butyl-l-t4-(2-carbomethoxy-benzoyl)benzyl]-4-chloro-5-[(lH-tetrazol-5-Yl)metbyl~imidazole The title compound was prepared from 2-butyl-1-[4-(2-carbomethoxybenzoyl)benzyl~-4-chloro-5-(cyano-methyl)imidazole by the procedure described in Example 26; NMR (200 MHz, DMS0-d6) ~ 8.00 (d, lH, J= 7Hz); 7.78 (t, lH, J= 7Hz): 7.70 (t, lH, J = 7Hz): 7.50 (d, 2H, J= 8Hz): 7.46 (d, lH, J= 7Hz): 7.05 (d, 2H, J= 8Hz):
5.35 (6, 2H): 4.20 (6, 2H): 3.57 (8, 3H): 2.52 (t, 2H, J= 7Hz): 1.52 (t of t, 2H, J= 7,7Hz): 1.27 (t of q, 2H, J= 7,7Hz): 0.70 (t, 3H, J= 7Hz). Anal. Calcd. for C25H25ClN6O3: C, 60.91: H, 5.11: N, 17.05- Pound:
C, 60.84: H, 5.12: N, 16.71. Ha66 Calcd. for C25H25ClN6O3: 492.1686. Eound: 492.1614.
PART B: Preparation of 2-Butyl-l-t4-(2-carboxy-benzoyl)benzyl]-4-chloro-5-t(lH-tetrazol-5-Yl)methyl~imidazole The title compound wa6 prepared from 2-butyl-1-t4-(2-carbomethoxybenzoyl)benzyl]-4-chloro-5-t(lH-tetrazol-5-yl)methyl]imidazole by the procedure de6cribed in Example 202, Part C: m.p. 228.0-229.5.
NMR (200 MHz, DMS0-d6) ~ 7.98 (d, lH, J= 7Hz): 7.73 (t, lH, J= 7Hz): 7.69 (t, lH, J= 7Hz): 7.55 (d, 2H, J= 8Hz): 7.38 (d, lH, J= 7Hz): 7.05 (d, 2H, J= 8Hz):
5.32 (6, 2H): 4.16 (6, 2H): 2.50 (t, 2H, J= 7Hz): 1.50 (t of t, 2H, J= 7,7Hz): 1.24 (t of q, 2H, J= 7,7Hz):
0.80 (t, 3H, J= 7Hz). Anal. Calcd. for C24H23ClN603:
C, 60.19: H, 4.84: N, 17.55. ~ound: C, 59.73: H, 4.61:
N, 17.82.
ExamPle 209 PART A: Preparation of 5-Aminomethyl-2-n-butyl-l-t4-(2-carbomethoxybenzoyl)benzyl]-4-chloroimidazole, chromium 6alt 5-Azidomethyl-2-n-butyl-1-~4-(2-carbomethoxy-benzoyl)benzyl]-4-chloroimidazole (4.24 g, 9.1 mmol, 1 eq), chromium (II) chloride (6.75 g, 54.7 mmol, 6 eq), acetone (40 mL) and water (13 mL) were mixed 231 I 3340~2 and 6tirred tthe chromium (II) chloride being added last). After Nz evolution had 6topped, the reaction mixture was diluted with 6aturated aqueou6 sodium bicarbonate (250 mL) and extracted with ethyl acetate (3 x 250 mL). The organic layers were dried (NgS04) and concentrated to give 601id6 which after wa6hing with et~er gave 2.92 g of white 601id (chromium 6alt of the product): m.p. 178.5-181Ø NMR (200 MHz, CDC13/DMSO-d6) ~ 8.85 (b6, lH); 8.05 (d, lH, J~ 7Hz):
7.57-7.25 (m, 4H); 7.36 (d, lH, J= 7Hz); 7.06 (bd, 2H, J= 7Hz); 5.67 (b6, 2H); 3.85 (b6, 2H); 3.67 (6, 3H);
2.60 (t, 2H, J= 7Hz); 1.~8 (m, 2H); 1.37 (t of q, 2H, J= 7,7Hz); 0.89 (t, 3H, J~ 7Hz). Mas6 Calcd. for C24H26ClN303: 439.1663. Found: 439.1663. Anal.
Calcd- for Cr(C24H26ClN33)2 N, 9.02. Found: C, 61.46; H, 5.59; N, 8.54.
PART B: Preparation of 2-Butyl-4-chloro~ 4-(2-carbomethoxybenzoyl)benzyl]-5-(methoxy-carbonYlaminomethyl)imidazole 5-Aminomethyl-2-butyl-1-[4-(2-carbomethoxy-benzoyl)benzyl]-4-chloroimidazole (chromium 6alt) (500 mg, 1.14 mmol, 1 eq) wa6 di6solved in a mixture of 1.00 N NaOH (1.14 mL, 1.14 mmol, 1 eq) and H20 (10 mL). Tetrahydrofuran may be added to a6si6t solvation. The 601ution was cooled to 0 when methyl chloroformate (0.176 mL, 2.28 mmol, 2 eq) in THF (5 mL) wa6 610wly dripped in, in five equal portion6, alternating with five portion6 of 1.00 N NaOH (total of 1.14 mL, 1.14 mmol, 1 eg). ~hen the addition wa6 complete, the mixture wa6 6tirred at room temperature for 4 hours. Water (100 mL) was added and the pH
adjusted to 5 with lN HCl. The aqueou6 wa6 extracted with ethyl acetate (3 x 100 mL), the organic layers -dried (MgS04) and stripped to give a white glass (560 mg). Flash chromatography in 100% ethyl acetate to 100% isopropanol yielded 280 mg of product as an oil. NMR (200 MHz, CDC13) ~ 8.10 (d, lH, J= 7Hz):
7.75 (d, 2H, J= 7Hz); 7.75-7.56 (m, 2H); 7.39 (d, lH, J= 7Hz): 7.02 (d, 2H, J= 7Hz~; 5.32 (6, 2H): 4.83 (m, lH): 4.28 (d, 2H, J= 7Hz): 3.70 (s, 3H); 3.57 (6, 3H);
2.58 (t. 2~, J= 7Hz); 1.72 (t of t, 2H, J= 7,7Hz);
1.37 (t of q, 2H, J= 7,7Hz); 0.92 (t, 3H, J= 7Hz).
Mass Calcd. for C26H28clN305 497.1717.
~ound: 497.1699.
T~e following intermediates were prepared or could be prepared by t~e procedure described in Example 209, Part B from the corre6ponding 5-(aminoalkyl)imidazole intermediate and t~e appropriate chloroformate or sulfonyl chloride.
R6 1 N~ R 1 3 3 4 0 9 2 ~ 1 Rl R6 R R MP(C) J~ O
ll ¦ n-butyl Cl CH2NHCOCH2CH3 3 2C ~
~ n-butyl Cl CH2NHCOCH2CH2CH3 " / 3 ll ¦ n-butyl Cl CH2NHCOCH
3 2 \CH3 ~ O
~ n-butyl Cl CH2NHCOCH2CH2CH2CH3 ~ O
ll ¦ n-butyl Cl CH2NHCOC6H5 3 2 ~
~ 0 1I J n-butyl Cl CH2NHCOCH2C6H5 ~ n-butyl Cl CH2-NH-502-CH3 163.0-168.0 234 1 3340~2 PA~T C: Preparation of 2-Butyl-4-chloro-1-t4-(2-carboxybenzoyl)benzyl]-5-(methoxy-carbonYlaminomethyl)imidazole Using the procedure of Example 202, Part C (wit~
or without refluxing), 2-butyl-1-t4-(2-carboxybenzoyl)-benzyl]-g-chloro-S-(methoxycarbonylaminomethyl)imid-azole wa~ prepared from 2-butyl-1-~4-(2-carbomethoxy-benzoyl)benzyl]-4-chloro-5-(methoxycarbonylamino-methyl)imidazole: mp . 6ublime6. NMR (200 MHz, DMS0-d6) ~ 13.17 (bm, lH): 7.97 (d, lH, J~ 7Hz):
7.71 (t, lH, Jz 7Hz): 7.63 (t, lH, J= 7Hz): 7.56 (d, 2H, J= lOHz): 7.50 (m, lH): 7.36 (d, lH, J= 7Hz): 7.03 (d, 2H, J= lOHz): 5.31 (8, 2H): 4.06 (d, 2H, J= 7Hz):
2.46 (t, 2H, J- 7Hz): 1.48 (t of t, 2H, J= 7,7Hz):
1.22 (t of q, 2H, J= 7,7Hz): 0.78 (t, 3H, J~ 7Hz).
Anal. Calcd. for C25H26ClN305: C, 62.05: H, 5.42: N, 8.68. Found: C, 61.97: H, 5.58: N, 8.40. Ma~ Calcd.
for C25H26ClN305: 483.1561. ~ound: 483.1560.
Examples 210-216 in Table 15 were prepared or could be prepared by t~e procedure de6cribed in Example 209, Part C using t~e appropriate ~tarting material.
Table 15 1 3340q2 R61 N~ R8 ~
No. _ R R R MP(C) o "
211 C02H n-butyl Cl CH2NE~COCH2CH2CH3 212 C02H n-butyl Cl CH2NHC-OCH\
"
213 C02H n-butyl Cl CH2NHCCH2CH2CH2CH3 o 214 C02H n-butyl Cl CH2NHCOC6H5 215 C02H n-butyl Cl CH2NHSCH3 (oil)a oo 216 C02H n-butyl Cl CH2NHCOCH2C6H5 a NMR (200 M~z, CDC13) ~ 7.97 (d, lH, J~
7Hz); 7.71-7.50 (m, 4H); 7.45 (d, lH, J=
7Hz); 6.95 (d, 2H, J= 8Hz); 5.23 (6, 2H);
4.15 (~, 2H); 2.57 (t, 2H, J= 7Hz); 1.67 (t of t, 2H, J= 7,7Hz); 1.36 (t o q, 2H, J=
7,7Hz); O.B7 (t, 3H, J= 7Hz).
Example 217 1 3 3 4 0 ~ ~
PART A: Preparation of 2-Butyl~ 4-(2-carbo-methoxybenzoyl)benzyl]-4-chloro-5-[(tri-fluoromethYl6ulfonamido)methyllimidazole Triflic anhydride (0.21 mL, 1.25 mmol, 1.1 eq) was ~lowly added to a pyridine (20 mL) 601ution of the chromium 6alt of 5-aminomethyl-2-butyl-1-[4-(2-carbomethoxybenzoyl)benzyl~-4-chloroimidazole (0.50 g, 1.1 mmol, 1.0 eq) at 0C. The ~olution was allowed to warm to room temperature. After l.S hour, 1.5 equivalent~ of triflic anhydride were added at 0. After an additional 4 hour6 at room temperature, water (200 mL) wa~ added and the pH adjusted to 5.
The aqueou6 was extracted with ethyl acetate (3 x 100 mL) and the organic layers dried (MgSO4) and concentrated to yield 150 mg of a yellow oil which was used as i~ for the subsequent hydrolyci6 ~tep.
NMR (200 MHz, CDC13) ~ 8.33 (bm, lH); 7.96 (d, lH, J= 7Hz); 7.64 (d, 2H, J= 10Hz); 7.56 (t, lH, J=
7Hz); 7.48 (t, lH, J= 7Hz); 7.28 (d, lH, J= 7Hz);
6.92 (d, 2H, J= 10Hz); 5.21 (fi, 2H); 4.14 (~, 2H);
3.17 (6, 3H); 2.48 (t, 2H, J= 7Hz); 1.55 (t of t, 2H, J= 7,7Hz); 1.24 (m, 2H); 0.79 (t, 3H, J= 7Hz).
5 PART B: Preparation of 2-Butyl-l-t4-(2-carboxy-benzoyl)benzyl~-4-chloro-5-t(trifluoro-methylsulfonamido)methYl~imidazole 2-Butyl-l-t4-(2-carbomethoxybenzoyl)ben2yl~-4-chloro-5-t(trifluoromethyl~ulfonamido)methyl~imidazole (150 mg, 0.26 mmol, 1 eq), 1.000 N NaOH (0.55 mL, 0.55 mmol, 2.1 eq), methanol (20 mL), and water (0.5 mL) were mixed and stirred for 5 hour~ at room temperature under N2. The solvent was removed in vacuo. Water (50 mL) was added and the pH was adju6ted to g with 1 N HCl. Tan 601idfi precipitated. The6e were collected and dried to yield 89 mg. NMR (200 MHz, DMSO-d6) ~ 7.98 (d, lH, J= 7Hz); 7.70 (t, lH, J= 7Hz): 7.68 (t, lH, J=
7Hz); 7.63 ld, 2H, J= lOHz): 7.37 (d, lH, J- 7Hz) 7.10 (d, 2H, J= lOHz): 5.34 (s, 2H): 4.20 (s, 2H):
2.50 (t, 2H, J= 7Hz): 1.49 (t of t, 2H, J= 7,7Hz):
1.27 (t of q, 2H, J= 7,7Hz): 0.80 (t, 3H, J= 7Hz). Ma66 calcd. for C24H23C1~3N305S:
557.0999- Pound: 557.0988 Example 218 PART A: Preparation of 2-Butyl-l-t4-(2-carbomethoxy-benzoyl)benzyl]-5-t(4-carbomethory-1,2,3-triazol-1-yl)methyl]-4-chloroimidazole and 2-butyl-1-14-(2-carbomethoYybenzoyl)benzyl]-5-[(5-carbomethoYy-1,2,3-triazol-1-yl)methyl]-4-chloroimidazole 5-Azidomethyl-2-butyl-4-chloro-1-t4-(2-carbo-methoxybenzoyl)benzyl]imidazole (0.50 g, 1.07 mmol, 1 eq), methyl propiolate (0.95 mL, 10.7 mmol, 10 eq) and toluene (20 mL) were mixed and refluxed under N2 for 3 hour6. The reaction mixture wa6 concentrated and the re6idue fla6h chromatographed over silica gel in 75:25 hexane/ethyl acetate. The two regioi60mer6 were separated to give 10 mg of the fa6ter eluting i60mer a6 a gla66 and 330 mg of the 610wer a6 a solid.
The 610wer i60mer could be further purified by wa6hing with ethyl acetate to give 190 mg of white cry6talline 601id. Pa6ter eluting i60mer: NMR (200 MHz, CDC13) 8.06 (d, lH, J= 8Hz) 7.96 (6, lH): 7.73-7.54 (m, 4H):
7.37 (d, lH, J= 8Hz); 6.86 (d, 2H, J= 8Hz): 5.76 (6, 2H); 5.41 (6, 2H); 3.90 (6, 3H): 3.68 (6, 3H): 2.56 (t, 2H, J= 7Hz); 1.67 (t of t, 2H, J= 7,7Hz); 1.35 -(t of q, 2H, J= 7,7Hz); 0.86 (t, 2H, J= 7Hz). Ma66 calcd. for C28H28N505Cl: 549.1778. Found: 549.1860.
Slower eluting isomer: m.p. 163.5-167.0: NMR (200 MHZ, CDC13) ~ 8.06 (d, lH, J= 8Hz); 8.00 (8, lH);
7.72 ~d, 2H, J= 8Hz); 7.72-7.55 (m, 2H); 7.41 (d, lH, J= 7Hz); 6.96 (d, 2H, J= 8Hz); 5.40 (6, 2H); 5.23 (6, 2H); 3.95 (6, 3H); 3.69 (6, 3H~; 2.58 (t, 2H, J= 7Hz);
1.70 (t of t, 2H, J= 7,7Hz): 1.38 (t of q, 2H, J=
7,7Hz); 0.89 (t, 3H, J= 7Hz). Ma66 calcd. for C28H28N5O5Cl: 549.1778. Pound: 549.1763.
The intermediate6 6hown below were prepared or could be prepared by the procedure de6cribed in Example 218, Part A u6ing the appropriate 6tartinq material6, N ~
S ~
~0 ,~1~ R 13 R _ R R MP(C) n-butyl Cl CH2-N ~ N C2CH3 (oll) n-Bu i60mer6) n-butyl Cl CH2 ~ N C2CH3 n-butyl Cl CH2-N N`N NHS02CF3 n-butyl Cl CH2-N ~ N 2 3 co2~
n-butyl Cl CH2-N ~ N 2 3 n-propyl H CH2-N ~ N N 2CF3 Co2cH2c6H5 n-propyl H CH2-N ~N 2 3 -240 1 3~40q 2 a NMR (200 MHz, CDC13) shows a mixture of 2 regioi60mer6: ~ 8.08 (d, lH, J= 8Hz);
7.80-7.55 (m, 4H): 7.44-7.34 (m, lH); 7.28 (s, lH); 7.00-6.88 (m, 2H); 5.40 (6, 0.5 x 2H); 5.32 (6, 0.5 x 4H); 5.29 (6, 0.5 ~ 2H);
3.71 (6, 0.5 x 3H); 3.69 (6, 0.5 ~ 3H);
2.75-2.48 (m, 4H); 1.80-1.21 (m, 8H);
1.00-0.81 (m, 6H).
PART B: Preparation of 2-Butyl-1-~4-(2-carboxy-benzoyl)benzyl]-5-t(4-carboxy-1,2,3-triazol-l-yl)met~yl1-4-chloroimidazole and 2-butyl-1-[4-(2-carboxybenzoyl)benzyl]-5-~(5-carboxy-1,2,3-triazol-1-yl)methyl~-4-chloroimidazole The 610wer eluting i60mer in Example 218, Part A
(190 mg, 0.35 mmol, 1 eq), 0.5 N KOH in methanol (2.76 mL, 1.39 mmol, 4 eq) and 5 mL of water were mixed and refluxed overnight under N2. Water (50 mL) wa6 added and the pH adju6ted to 5. The aqueou6 mixture was extracted with ethyl acetate (3 x 50 mL), the organic fraction6 dried (MgSO4) and concentrated to give a re6idue which wa6 triturated with ether yielding 160 mg of 601id product. NMR (200 MHz, DMSO-d6 + py-d5) ~ 8.20 (d, lH, J= 8Hz): 7.86-7.63 (m, 4H); 7.57 (d, lH, J= 8Hz); 7.43 (6, lH); 7.04 (d, 2H, J= 10Hz); 6.84 (6, 2H); 6.63 (6, 2H); 2.62 (t, 2H, J= 7Hz); 1.65 (t of t, 2H, J= 7,7Hz); 1.30 (t of q, 2H, J= 7,7Hz); 0.81 (t, 3H, J= 7Hz). Ma66 calcd. for C26H24N5O5Cl-CO2:
477.1567. Found: 477.1593.
The fa6ter eluting isomer in Example 218, Part A
was hydrolyzed in a 6imilar fashion except that upon acidification in the work-up, 601id product precipi-tated, m.p. 149.0-152.5. NMR (200 MHz, DMSO-d6) ~
8.02 (6, lH); 8.02 (d, 2H, J= 7Hz); 7.74 (t, lH, J=
7Hz); 7.66 (t, lH, J= 7Hz): 7.50 (d, 2H, J= 7Hz); 7.37 (d, lH, J= 7Hz); 6.92 (d, 2H, J= 7Hz); 5.83 (s, 2H);
5.42 (s, 2H); 2.52 (t, 2H, J= 7Hz): 1.55 (t of t, 2H, J= 7Hz); 1.28 (t of q, 2H, J= 7,7Hz); 0.78 (t, 3H, J=
7Hz). Mass calcd. for C26H2gN505Cl~C02:
477.1567. F~und: 477.1479.
Examples in Table 16 were prepared or could be prepared by the procedure described in Example 218, Part B.
Table 16 N ~
R6 ~ N ~ R8 ~0 ~ R13 No _ R R R MP(C) 219 n-butyl Cl 2 N ~ N C02H (oil) isomers) 220 n-butyl Cl 2 ~ C02H
COOH OOH
221 n-butyl Cl2 ~ NHS02CF3 COOH
222 n-butyl ClCH2 N ~ N NHS02CF3 COO~I
-242 1 3340~2 a NMR (200 MHz, CDC13) ~ 8.03 (m, lH);
7.77-7.42 (m, SH); 7.33 (6, lH); 5.36 (s, 2H); 5.26 (6, 2H); 2.68-2.45 (m, 4H);
1.82-1.48 (m, 4H); 1.42-1.20 (m, 4H):
1.00-0.80 (m, 6H).
Example 223 PART A: Preparation of 1-(4-~ormylbenzyl)-2-butyl-4-chloro-5-hydroxymethylimidazole To a 601ution of 5.05 g of 1-(4-cyanobenzyl)-2-butyl-4-chloro-5-hydroxymethylimidazole in 350 mL of benzene at 25 was added dropwi6e 22.8 mL of dii60-butylaluminum hydride (0.15 M in toluene). The mixture wa6 warmed to 45 and 6tirred for 16 ~our6.
After cooling, the reaction mixture was poured in ice-cold 20% aqueou6 6ulfuric acid. Thi6 601ution wa6 allowed to warm to 25 and then 6tirred for 2 bour6.
The 601ution was cooled to 0, neutralized using aqueous sodium hydroxide and extracted with ethyl acetate. The combined organic phases were wa6hed with water and brine, dried over anhyd{ous sodium 6ulfate, filtered, and concentrated. Column chromatography on silica gel (elution: 0-20% ethyl acetate/benzene) provided 3.60 g of 1-(4-formyl-benzyl)-2-butyl-4-chloro-5-hydroxymethylimidazole; NMR
(200 MHz, CDC13) ~: 9.96 (6, lH); 7.47 (A2M2, 4H);
5.26 (6, 2H); 4.42 (s, 2H); 2.54 (t, 2H); 1.64 (quint., 2H); 1.32 (6ext., 2H); 0.86 (t, 3H).
PART B: Preparation of 1-[(2'-Cyano-trans-6tilben-4-yl)methyl]-2-butyl-4-chloro-5-~ydroxy-methylimidazole To a solution of 0.98 g of a-bromo-o-tolu-nitrile in 25 mL of dimethylformamide at 2~ was added 3s 1.40 g of triphenylphosphine. The mixture was stirred 243 1 3340~2 at 80 for 3 hour6, then treated with 1.53 g of 1-(4-formylbenzyl)-2-butyl-4-chloro-5-hydroxymethylimid-azole, followed immediately by 0.54 g of 60dium methoxide, and the mixture wa6 diluted witb water and extracted with benzene. The organic phase6 were com-bined and wa~ed with water and brine, dried over anhydrous 60diu~ 6u~fate, filtered, and concentrated.
Column chromatograp~y on ~ilica gel (elution: 0-20%
ethyl acetate/benzene) afforded 0.45 ~ of 1-t(2'-cyano-tran6-6tilben-4-yl)methyl~-2-butyl-4-chloro-5-hydroxymethylimidazole; NMR (200 MHz, CDC13):
8.01 (d, lH); 7.85 (d, lH): 7.73 (t, lH); 7.47 (t, lH); 7.44 (AB, 2H, J=16.3); 7.38 (A2B2, 4H); 5.28 (6, 2H); 5.24 (t, lH); 4.34 (d, 2H); 2.49 (t, 2H);
1.47 ~quint., 2H); 1.24 (6ext., 2H): 0.79 (t, 3H).
PART C: l-t(2'-Carboxy-tran6-6tilben-4-yl)methyl]-2-butyl-4-chloro-5-hydroxYmethylimidazole A 601ution of 0.40 g of l-t2'-cyano-tran6-6tilben-4-yl)methyl~-2-butyl-4-chloro-5-hydroxymethyl-imidazole in 20 mL of ethylene glycol and 12 mL of 10%
aqueou6 60dium hydroxide was refluxed for 5.5 hour6.
After cooling, the reaction mixture was filtered, and the 601vent was removed in vacuo. The re6idue wa6 di6solved in water, and the 601ution wa6 acidified to pH 3.5 u6ing hydrochloric acid and the re~ulting emul6ion was extracted ~ith chloroform. The combined organic pha6e6 were wa6hed with saturated aqueou6 60dium chloride ~olution, dried over anhydrou6 60dium sulfate, filtered and concentrated. Column chroma-tography on 6ilica gel (elution:5t methanol/chloroform) afforded 0.12 g of 1-[(2'-carboxy-trans-stilben-4-yl)-methyl]-2-butyl-4-chloro-5-hydroxymethyli~idazole; NMR
(200 MHz, CDC13): ~ 8.08-8.00 (m, 2H); 7.71 (d, lH); 7.57-7.47 (m, 3H); 7.34 (t, lH); 7.01-6.92 (m, 3H); 5.21 (6, 2H); 4.50 (6, 2H); 2.60 (t, 2H); 1.62 (quint, 2H); 1.31 (6ext., 2H); 0.03 (t, 3H).
Example 225 PART A: Preparation of N-(4-Benzyloxybenzyl)glycine ethyl e6ter To a 6uspension of 11.0 g of glycine ethyl e6ter hydrochloride in 100 mL of dimethylformamide at 25 wa6 added 22.0 mL of triethylamine. To the re6ulting milky 6u6pension wa6 added 9.08 g of 4-benzyloxybenzyl chloride in 50 mL of DMF dropwi6e over 0.5 hour. The mixture wa6 6tirred for 16 hour6 at 25. The reaction mixture wa6 diluted with diethyl ether and then fil-tered to remove the precipitated triethylamine bydro-chloride. The re6ulting ~olution wa6 concentrated invacuo, and the re6idue was di6~01ved in ethyl acetate.
The 601ution wa6 wa6hed with water and brine, dried over anhydrous 60dium 6ulfate, filtered, and concen-trated. Kugelrohr di6tillation provided 5.90 q of N-(4-benzyloxybenzyl)glycine ethyl ester tbp 160-180 (0.015 torr.)]; NMR (200 MHz, CDC13): ~ 7.43-7.27 (m, 5H); 7.06 (A2B2, 4H); 5.01 (6, 2H); 4.14 (quart., 2H);
3.71 (s, 2H); 3.36 (6, 3H); 2.01 (bs, lH): 1.24 (t, 3H).
PART B: Preparation of N-(4-Benzyloxybenzyl)-N-formyl-qlycine ethyl ester A 601ution of 5.83 g of N-(4-benzyloxybenzyl)-qlycine ethyl e6ter, 0.86 mL of formic acid, and 20 mL
of xylene was refluxed for 2 hour6 u6ing a Dean-Stark trap to remove the water produced in tbe reaction.
After cooling, t~e reaction mixture was wa6hed with 20~ aqueous formic acid, water, 6aturated 60dium bicarbonate solution, water, and brine. Finally the mixture was dried over anhydrous 60dium 6ulfate, -filtered, and the filtrate wa6 concentrated to furni6h 6.23 g of crude N-(4-benzyloxybenzyl)-N-formyl glycine ethyl e6ter, u6ed in the followinq reaction without further purification.
PART C: Preparation of 1-(4-Benzyloxybenzyl)-5-carbo-methoxy-2-(3H)-imidazolethione To a su6pension of 1.10 g of 60dium methoxide in 35 mL of tetrahydrofuran at 10 there wa6 added in one portion, a 601ution of 6.23 g of N-(S-benzyloxybenzyl)-N-formyl glycine ethyl e6ter and 3.46 mL of methyl formate in 15 mL of TH~. The mixture wa6 6tirred at 10 for 1 hour and then at 25 for 16 hour6. The 601vent wa~ removed in vacuo and t~e re6idue di6601ved in 36 mL of methanol. To thi6 601ution wa6 added 3.57 mL of conc. hydrochloric acid, and the mixture was 6tirred at 40 for 0.5 hour. A 601ution of 2.80 g of pota66ium thiocyanate in 6 mL of water wa6 added, and the re6ultin~ mixture wa6 6tirred for 16 hour6 at 40. Finally, 40 mL of water wa6 added, and the mixture wa6 allowed to cool to 25. The precipitated 601id wa6 recovered by filtration to afford 3.60 g of 1-(4-benzyloxybenzyl)-5-carbomethoxy-2(3H)-imidazole-thione; NMR (200 MHz, CDC13): ~ 11.25 ~b6, lH):
8.05 (6, lH); 7.39 (m, 5H); 7.03 (A2B2, 4H); 5.06 (6, 2H); 4.56 (6, 2H); 3.81 (6, 3H).
PART D: Preparation of 1-(4-Benzyloxybenzyl)-2-propyl-thio-S-carboethoxyimidazole To 60 mL of ethanol at 25 wa6 added portionwise 0.30 g of 60dium metal. After the 60dium metal ha6 reacted 3.54 g of 1-(4-benzyloxybenzyl)-5-carbomethoxy-2-(3H)-imidazolethione wa6 added followed immediately by 2.24 mL of l-iodopropane, and the mixture wa6 6tirred at 24 for 3 hour6. At thi6 point, the 246 1 3~4092 solvent was removed in vacuo, and the residue was dissolved in methylene chloride. This solution was washed with water and brine, dried over anhydrous sodium sulfate, iltered, and concentrated to furnish 3.46 g of crude 1-(4-benzyloxybenzyl)-2-propylthio-5-carboethoxyimidazole, used in a subsequent reaction without further purification: NMR (200 MHz, CDC13):
.77 (s, lH); 7.45-7.32 (m, 5H): 7.03 (A2B2, 4H); 5.49 (s, 2H); 5.03 (s, 2H); 4.28 (quart., 2H):
3.20 (t, 2H); 1.32 (t, 3H); 1.02 (t, 3H).
The following intermediates were prepared or could be prepared employing the above procedure.
~7 N
R6 J~ N ~R8 n-C6H13S- H C02CH2CH3 n-C4HgS- H CO2CH2CH3 0 PART E: Preparation of 1-(4-Benzyloxybenzyl)-2-propyl-thio-5-hydroxymethylimidazole A solution of 2.05 g of 1-(4-benzyloxybenzyl)-2-propylthio-5-carboethoxyimidazole in 10 mL of tetra-hydrofuran was added dropwise to 10 mL of lM lithium 3S aluminum hydride in THF at 0 such that the reaction temperature remained below 5. The resulting solution then was stirred at 0 for 1 hour. At this point, the reaction mixture was quenched by 6equential dropwise addition of 0.40 mL of water, 0.40 mL of 15~ aqueous sodium hydride, and 1.20 mL of water. The resulting suspension was filtered employing diethyl ether, and the filtrate was concent~ated to furnis~ 1.55 g of l-(g-benzyloxybenzyl)-2-propylthio-5-hydroxymethyl- -imidazole; NMR (200 MHz, CDC13): ~ 7.41-7.29 (m, 5H); 7.03-6.86 (m, 5H); 5.22 (s, 2H); 5.01 (s, 2H):
4.45 (s, 2H); 3;01 (t, 2H): 2.32 (bs, lH): 1.66 (sext., 2H); 0.97 (t, 3H).
The intermediates 6hown below were prepared or could be prepared employing the above procedure.
N ,,R
R6~N ~R8 n-C6H13S- 2 n-C4HgS- 2 2q8 PA~T F: Preparation of 1-(4-Hydroxybenzyl)-2-propyl-_thio-5-hydroxy~ethylimidazole A solution of 1.40 g of 1-(4-benzyloxybenzyl)-2-propylthio-5-hydroxymethylimidazole in 15 mL of trifluoroacetic acid was refluxed for 0.25 hour.
After cooling, the reaction was poured into water contain~ng an excess of sodium bicarbonate, and the resulting emulsion was extracted with ethyl acetate.
The combined organic phases were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated. Column chromatography on silica gel (elution: 0-5% methanol/chloroform) afforded 0.28 9 of l-(4-hydroxybenzyl)-2-propylthio-S-hydroxymethyl-imidazole: ~R (200 MHz, DMSO-d6): ~ 9.41 (s, lH); 6.88 (s, lH); 6.79 (A2B2, 4H); 5.14 (t, lH);
5.07 (s, ZH): 4.33 (d, 2H); 2.89 (t, 2H); 1.54 (sext., 2H); 0.88 (t, 3H).
These intermediates were prepared or could be prepared employing the above procedure.
N R
R6l~R8 ~
n-C6H13S- 2 n-CgHgS- 2 249 l 334092 STEP G: Preparation of 1-[4-(2-Cyanobenzyloxy)benzyl]-2-Pro~ylthio-5-hydroxYmethylimidazole The title compound was prepared from 1-(4-hydroxybenzyl)-2-propylthio-5-hydroxymethylimidazole using the procedure described in Example 192, Part C; NMR (200 MHz, CDCl3): ~ 7.66 (m, 3H); 7.43 (m, lH); 7.03 (2, lH); 6.99 (A2B2, 4H); 5.23 (s,2H); 5.22 (s, 2H); 4.47 (s,2H); 3.04 (t, 2H); 1.69 (sext., 2H); 0.98 (t, 3H).
The following 2-mercaptoimidazoles shown below were prepared by the procedure illustrated above.
~ 7 ~ 1~3 x~
X
CN
n-C6Hl3S- H CH2OH 4-OCH
CN
n-C4HgS- H CH2OH 4-OCH
0 STEP H: Preparation of 1-[4-(2-Carboxybenzyloxy)-benzyl]-2-propylthio-5-hydroxymethylimidazole A solution of 0.23 g of 1[4-(2-cyanobenzyloxy)-benzyl]-2-propylthio-5-hydroxymethylimidazole in 17 ml of ethylene glycol and 7 ml of 10~ aqueous sodium hydroxide was refluxed for 14 hours. After cooling, the reaction mixture was filtered, and the solvent was ~, removed in vacuo. The residue was dissolved in water, and the solution was acidified to pH 3.5 using hydrochloric acid. The precipitated solid was recovered by filtration and recrystallized from aqueous ethanol to furnish 0.094 g of 1-[4-(2-carboxybenzyloxy)benzyl]-2-propylthio-5-hydroxymethylimidazole; NMR (200 MHz, DMS0-d6); ~ 13.12 (bs, lH); 7.93 (d, lH); 7.58 (m, 2H); 7.45 (m, lH); 6.99 (A2B2, 4H);
p 6.98 (s, lH); 5.42 (s, 2H); 5.25 (bs, lH); 5.17 (s, 2H); 4.35 (s, 2H); 2.92 (t, 2H); 1.54 (sext., 2H); 0.89 (t, 3H).
The following 2-mercaptoimidazoles of Table 17 were prepared or could be prepared by the procedure illustrated above.
Table 17 R6 ~ N ~ R8 ~R13 Ex. x ~ 13 NO. R6 R7 R8 n-c6H135- H CH20H 4-0CH2 _~
Co2H
226 n-C4H95- H CH20H 4-OCH
X
.
Example 227 PART A: ~reparation of 1-(4-Nitrobenzyl)-2-butyl-4-chloroimidazole-5-aldehyde A mixture of 1 g of 1-(4-nitrobenzyl)-2-butyl-4-chloro-5-hydroxymethyl imidazole and 5 g of activated MnO2 in CH2C12 wa6 6tirred at room temperature for 16 hour6. The reaction mixture wa6 filtered through celite and the filtrate wa6 concentrated to give a thick oil which wa6 purified by fla6h column chroma-tography on 6ilica gel (Hexane:ethyl acetate=1.5:1 elution). The de6ired compound was obtained as a colorle66 solid, 0.76 g: m.p. 88-89; NMR (200 MHz, CDC13): ~ 9.74 (2, lH); 5.64 (s, 2H); 2.63 (t, 3H, J=7.4 Hz); 1.68 (m, 2H); 1.34 (m, 2H): 0.89 (t, 3H, J=7.3 Hz).
PART B: Preparation of 3-tl-(4-Nitrobenzyl)-2-butyl-4-chloroimidazol-S-yl~propenoic acid, ethyl e6ter, E and Z i60mer6 A mixture of 1.2 g of 1-(4-nitrobenzyl)-2-butyl-4-chloroimidazole-5-aldehyde and 1.5 g of (carboxy-methylene)triphenylpho6phorane in 50 mL of benzene was refluxed for 2 hours. The reaction mixture wa6 concentrated and the re6idue wa6 purified by fla6h column chromatography on 6ilica gel (Hexane:EtOAc=3:1 elution). The major product, the E i60mer, wa~ eluted first and wa6 obtained a6 a thick oil initially which solidified to give an amorphou6 601id, 1.2 g. The minor product, the Z i60mer was eluted next and wa6 i601ated as a thick liquid, 85 mg. E i60mer: NMR
(200 MHz, CDC13): 7.3 and 6.53 (d, 2H, 5=16 Hz):
5.3 (s, 2H); 2.62 (t, 2H, J=7.3 Hz); 1.69 (m, 2H);
1.28 (m, 5H); 0.89 (t, 3H, J=7.3 Hz).
Z isomer: NMR (200 MHz, CDC13): (key peaks only) ~ 6.45 and 6.02 (d, 2H, J=11.8 Hz); 5.17 (s, 2H).
`~ 252 1 3340~2 PART C: Preparation of 3~ (4-Nitrobenzyl)-2-butyl-4-chloroimidazol-5-Yllpropen-l-ol~ E i60mer A 601ution of 0.5 g of 3-11-(4-nitrobenzyl)-2-butyl-4-chloroimidazol-5-yl]propenoic acid, ethyl e6ter, E isomer in 20 mL of TH~ wa~ cooled with an ice batb, 1.7 mL of 1.5 M dii60propylaluminum hydride (in toluene) wa6 added 610wly. The cooling bath wa6 removed and the reaction ~ixture wa6 6.tirred at room temperature for 1 hour. The reaction mixture wa6 then guenched with 3 mL of conc. NH~Cl ~oluti~n and the mixture wa6 6tirred for an additional 30 minute6.
During thi~ period an exten6ive gel~ e ~aterial formed. The reaction mixture wa6 further diluted with ether and filtered through Celite*. ~he filtrate wa6 concentrated and the crude product wa6 purif~ed by fla~h column chromatography on 6ilica gel (Hexane:
EtOAc~l:l elution). The de~ired co~pound wa6 obtained a6 a thic~ liguid; NMR (200 MHz, CDC13): ~ 6.5-6.15 (m, 2H): 5.21 (6, 2H): 4.25 (d, 2H, J.4.5 Hz): 2.35 (t, 3H, J~7.4 Hz): 1.68 (m, 2H): 1.34 (m, 2H): 0.86 (t, 3H, J=7.4 Hz).
PART D: Preparation of 3-tl-(4-Aminobenzyl)-2-butyl-4-chloroimidazol-5-Yl~propen-l-ol~ ~ i60mer A mixture of 0.2 g of 3-~1-(4-nitrobenzyl)-2-butyl-4-chloroimidazol-5-yl]propen-1-ol, 0.15 g of iron and 0.3 mL of glacial acetic acid in 10 mL of ab~olute ethanol wa6 refluxed for 1 bour. The reac-tion mixture wa6 concentrated to dryne66 and the re6idue wa6 di6601ved in 20 mL of water and the 601u-tion wa6 made basic to pH 8 by adding ~2C03. The mixture was then extracted with ethyl acetate and the ethyl acetate layer was wa6hed with water. The organic layer was concentrated to give a crude product wbich wa~ purified by flash 6ilica gel column chromatography * trade mark 1 3340~2 (ethyl acetate elution). A pure product was obtained as an amorphou6 solid; NMR (200 MHz, CDC13): ~ 6.76 and 6.62 (dd, 4H, J=8.5 Hz); 6.42-6.22 (m, 2H); 2.57 (t, 2H, J=7.3 Hz), 1.65 (m, 2H); 1.33 (m, 2H); 0.87 5 (t, 2H, J=7.3 Hz).
PART F: Preparation of 3-~1-(4-(2-Carboxybenzamido)-benzyl)-2-butyl-4-chloroimidazol-5-yl]-Propen-l-ol~ E isomer To a solution of 95 mg Of 3-tl-(4-aminobenzYl)-2-butyl-4-chloroimidazol-5-yl]propen-1-ol in 2 mL of CHC13 wa~ added 45 mg of phthalic anhydride and the mixture was stirred at room temperature for 1 hour.
During thi6 period of time the initially clear 601u-tion became turbid and produced ~olid. The reaction mixture was diluted wit~ 2 mL of ether and the solid wa6 collected by filtration and washed with ether.
The desired product was obtained as a tan solid, 115 mg, m.p. 150-151; NMR (10~ DMS0-d6/CDC13): ~ 9.94 (5. lH); 7.71 and 6.93 (d, 4H, J=8.3 Hz); 6.36 (m, 2H); 5.1 (s, 2H); 4.18 (d, 2H, J=3.9 Hz); 2.6 (t, 3H, J=7.4 Hz): 1.68 (m, 2H): 1.34 (m, 2H): 0.89 (t, 3H, J=7.4 Hz).
ExamPle 228 PART A: Preparation of 3-t2-Butyl-4-chloro-1-(4-aminobenzyl)imidazol-5-yl]propenoic acid ethYl e6ter, E i60mer A mixture of 0.5 g of 3-t2-butyl-4-chloro-1-(4-nitrobenzyl)imidazol-5-yl]propenoic acid et~yl ester (E isomer) prepared from Part B of Example 227, 1 g of iron and 2 mL of glacial acetic acid in 30 mL of absolute ethanol was refluxed for 1 hour. The reac-tion mixture was concentrated to dryness and the residue was dis601ved in 50 mL of H20. The aqueous 601ution wa6 adju6ted to pH 8 by K2C03 and was extracted witb ethyl acetate. Tbe crude product obtained upon concentration of tbe etbyl acetate extract was purified by flash 6ilica gel column chromatography (hexane:ethyl acetate.l:l elution).
The de6ired compound was obtained as a thic~ colorless oil, 0.35 g.
PART B: Preparation Of 3-t2-Butyl-4-chloro-1-(~-(2-carboxybenzamido)benzyl)imida201-S-yl~-ProPenoiC acid etbyl ester, E isomer A mixture of 361 Dg of the aniline derivative obtained from Part A and 150 mg of phthalic anhydride in 3 mL of chloroform was 6tirred at room temperature for 1 hour. The reaction ~ixture was concentrated and tbe residue was triturated iD ethyl ether. The resulting 601id wa6 collected and dried to give a colorless 601id, 450 mg, m.p. 180-181. NMR (CDC13, 5~ DMS0-d6) ~ 0.91 (t, 3H, J~ 7,1Hz): 1.1-1.4 (m, 5H): 1.60 (q, 2H, J~ 7,3Hz): 2.71 (t, 2H, J. 8,4Hz):
4.17 (q, 2H, J~ 7,3Hz); 5.23 (6, 2H): 6.46 ~ 7.38 (d each, 2H, J. 16,1Hz): 6.0-8.0 (m, 8H), 10.2 (6, lH).
ExamPle 229 PART A: Preparation of 1-(2'-Carbomethoxybi-phenyl-4-yl)metbyl-2-butyl-4-chloro-imidazole-5-carboxaldebyde A mixture of 0.68 g of the ~ydroxymethyl precursor prepared in Example 85, Part C and 3.4 q of activated MnO2 in 30 mL of CHC13 wa6 6tirred at room temperature for 4 hours. Tbe reactioD mixture was then filtered through Celite and the filtrate wa6 concentrated to give a thic~ oily residue which was purified by flash chromatograpby on silica gel (hexane:ethyl acetate=2:1 elution). Tbe de6ired ,, 1 3340~2 aldehyde was obtained as a thic~ colorles6 oil, 0.5 q NMR (CDC13): 9.78 (6, lH); 5.6 (8, 2H): 3.63 (6, 3H); 2.63 (t, 3H, J=7.4 Hz); 1.68 (m, 2H): 1.34 (m, 2H); 0.89 (t, 3H, J=7.4 Hz).
PART B: 4-tl-(2'-Carbomethoxybiphenyl-4-yl)methyl-2-butyl-4-chloroimidazol-5-yl]-3-buten-2-one, E isomer A mixture of 0.5 g of 1-(2'-carbomethoxybi-phenyl-4-yl)methyl-2-butyl-4-chloroiDidazole-5-carboxaldehyde and .04 g of l-triphenylpho6phoran-ylidene-2-propanone in 20 mL of benzene wa6 refluxed for 16 hour6. The reaction misture was concentrated to give an oily re6idue whic~ wa6 purified by fla6h chromatography on 6ilica gel (hexane:ethyl acetate.l:l elution). The de6ired compound va6 obtained a6 a thick yellowi6h liquid, 0.46 g: NMR (200 MHz, CDC13):
7.9-6.8 (m, lOH): 5.24 (6, 2H): 3.62 (6, 3H): 3.62 (6, 3H): 2.69 (t, 2H, J=7.4 Hz): 2.26 (6, 3H): 1.72 (m, 2H): 1.38 (m, 2H): 0.91 (t, 3H, J=7.4 Hz).
PART C: Preparation of 4-tl-(2'-Carbomethoxybi-phenyl-4-yl)metbyl-2-butyl-4-chloro-imidazol-5-Yl]-3-buten-2-ol~ ~ i60mer A 601ution of 0.45 g of the compound prepared in Part B in 5 mL of methanol was cooled with ice and 0.2 g of NaBH4 wa6 added portionwi6e. After all the NaBH4 wa6 added the reaction mixture wa6 6tirred for 10 minute6. The reaction mixture wa6 concentrated to dryne66 and the re6idue wa6 treated with 3 mL of 6atd.
NH4Cl and the mixture wa6 6tirred at room temperature for 10 min. The mixture wa6 then extracted with ethyl acetate and the ethyl acetate extract was concentrated t~ give a thick liquid, 0.45 g; NMR (200 MHz, CDC13):
6.45-6.15 (m, 2H,): 5.16 (6, 2H); 4.34 (m, lH, ): 3.67 (8, 3H).
Example 230 PART A: Preparation of 1-(4-nitrobenzyl)-2-butyl-4-chloro-5-(2-phenylethen-1-yl)imidazole, E i60mer A colution of 0.4 g of benzyltriphenylpho6-phonium chloride in 20 mL of dried THF wa6 cooled to -30. To the above solution wa6 added 0.65 mL of 1.6 M n-BuLi dropwi6e. A6 the BuLi wa6 added the colution turned to deep orange color. After 6tirring for 10 min. at -30, 0.32 ~ of 1-(g-nitrobenzyl)-2-butyl-4-chloroimidazole-S-aldehyde wa6 added and the reaction mixture wa6 allowed to warm up to room temperature and 6tirred at room temperature for 2 hour6. The reaction mixture wa6 guenched with 2 ~L of 6aturated NH4Cl solution and diluted with ethyl acetate, and the etbyl acetate 601ution wa~ wa6hed with water and a brine 601ution. Evaporation gave a thic~ oily re6idue which wa6 purified by the fla6h ~ilica gel column chroma-tography (hexane:ethyl acetates3:1 elution) to give a thick yellow oil, 0.39 g, PART B: Preparation of l-t4-(2-Carboxybenzamido)-benzyl]-2-butyl-4-chloro-5-(2-phenylethen-l-yl~imidazole, E i60mer The compound wa6 prepared from the compound of Part A by the procedure de6cribed in Example 227, Part6 D and E; m.p. 111-113 (dec).
ExamPle 231 PART A: Preparation of 3-12-Butyl-4-chloro-1-(4-nitrobenzyl)imidazol-5-yl]-3-propen-1-ol acetate, E i~omer A mixture of 1 g of 3-tl-(4-nitrobenzyl)-2-butyl-4-chloroimidazol-5-yl]propen-1-ol obtained from Part C
of Example 227, 1 mL of acetic anhydride and 2 mL of pyridine in 20 mL of CH2C12 was stirred at room temperature for 16 hours. The reaction mixture was diluted with 100 mL of ethyl acetate and the organic layer was washed with H20. T~e crude product obtained upon concentration of the organic layer was purified by flash silica gel chromatography (hexane:
ethyl acetate=l:l elution) to give the desired acetate as a thick colorless oil, O.9S g.
0 PART B: Preparation of 3-~2-Butyl-4-chloro-1-(4-aminobenzyl)imidazol-5-yl]-3-propen-1-ol acetate, E isomer The nitro compound obtained from Part A was reduced to t~e amino compound by the conditions described in Part D of Example 227. The desired compound wa6 obtained as a colorles~ thic~ oil.
PART C: Preparation of 3-t2-Butyl-4-chloro-1-(4-(2-carboxybenzamido)benzyl)imidazol-S-yl]-3-propen-l-ol acetate, E isomer The phthalamic acid derivative was obtained from the aniline derivative obtained from Part B and phthalic anhydride by the method described in Part E
of Example 227. The desired compound was obtained as a colorless solid, m.p. 84-87.
NMR (CDC13) ~ 0.91 (t, 3H, J= 7,1Hz); 1.2 (m, 2H); 1.7 (m, 2H); 2.0 (s, 3H); 2.7 (t, 2H, J= 7,4Hz); 4.57 (d, 2H, J= 5,4Hz); 5.06 (s, 2H);
6.24 (m, 2H); 6.9-8.0 (m, 8H); 8.8 (s, lH).
Example 232 Preparation of 3-tl-(4-((N-Trifluoromethane6ulfonyl)-anthranilamido)benzyl)-2-butyl-4-chloroimidazol-5-yl]-3-propen-1-ol acetate, E i60mer A mixture of 0.72 g of 3-t2-butyl-4-chloro-1-(4-aminobenzyl)imidazol-5-yl]-3-propen-1-ol acetate obtained from Example 231, Part B and 0.6 mL of tri-ethylamine in 20 mL of CH2C12 wa6 cooled with an ice bath. To thi6 solution was added 0.6 g of o-(tri-fluoromethane6ulfonamido)benzoyl chloride dropwi6e and the reaction mixture wa6 stirred at room temperature for 2 hour6. The reaction mixture wa6 then diluted with 100 mL of ethyl acetate, and the ethyl acetate 601ution wa6 wa6hed with vater, dried over Na2S04 and concentrated to qive a crude product which wa6 purified by a fla6h silica gel column chromatography (3% aceto-nitrile in ethyl acetate) to give the desired compound a6 a 601id, 1.05 g, m.p. 156-158; NMR (200 mHz, CDC13): ~ 12.9 (bs, lH); 8.12-6.91 (m); 6.3 (8);
5.09 (6); 4.61 (d, 2H, J=4.5 Hz); 2.04 (6, 3H).
ExamPle 233 Preparation of 3-tl-(4-((N-trifluoromethane6ulfonyl)-anthranilamido)benzyl)-2-butyl-4-chloroimidazol-5-yl]-Propen-l-ol~ E i60mer A mixture of 0.9 g of the compound of Example 232 and 3 mL of lN NaOH in 6 mL of metbanol wa6 6tirred at room temperature for 16 hour6. The reaction mixture was diluted with 50 mL of water and the aqueou6 601u-tion wa6 acidified to a pH of 3 with lN HCl to produceextensi~e solids which were collected and wa6hed with water. The 601id6 were then dried in vacuo to give O.85 g of the de6ired product, m.p. 129-131; NMR (200 MHz, 5% DMSO-d6/CDC13): ~ 11.15 (bs, lH); 8.02-6.95 (m, 8H); 6.5-6.3 (m, 2H); 5.13 (6, 2H); 4.19 (d, 2H, J=3.5 Hz).
-Example 234 1 3340~2 PART A: Preparation of 3-t2-Butyl-4-chloro-1-(4-nitrobenzyl)imidazol-5-yl]-2-(carboethoxy)-propanoic acid, ethyl ester The 60dium salt of diethyl malonate wa6 generated from 2.5 g of NaH (50% oil di6per6ion) and 8 mL of diethyl malonate in 100 mL of dried DMP with ice cooling. To the above 601ution wa6 added 5 g of the chloromethyl compound and the mixture wa6 6tirred at room temperature for 3 hours. The reaction mixture was 6tirred at room temperature for 3 hours. The reaction mixture was concentrated and the re6idue wa6 diluted with 100 mL of water. The aqueous layer was acidified to a pH of 6 by lN HCl and the product wa6 extracted with ethyl acetate. The crude product was purified by column chromatography'(Hexane:EtOAc=2:1 elution) which afforded the product a6 a thic~ yellow oil, 2.8 g.
PART B: Preparation of 3-t2-Butyl-4-chloro-1-(4-nitro-benzyl)imidazol-5-yl]propanoic acid methyl e6ter A mixture of 0.5 g of the compound from Part A
in 20 mL of 3N HCl wa6 refluxed for 2 hours. The reaction mixture was cooled and neutralized to a pH of 6 with 4N NaOH 601ution. The re6ulting gummy 601id6 were extracted into ethyl acetate and concentrated to give a thic~ yellow oil, 0.5 g. The propionic acid derivative wa6 di6solved in ethyl ether and was treated with diazomethane in ethyl ether to give a crude methyl e6ter which was purified by column chromatography (hexane:ethyl acetate=l:l) which afforded the product as a waxy 601id, 0.34 g.
-1 3S40~2 PART C: Preparation of 3-t2-Butyl-4-chloro-1-(4-(2-carboxybenzamido)benzyl)imidazol-5-yl]-propanoic acid methyl ester The nitro compound of Part B was reduced to the corresponding amino compound by methods previou61y described. A mixture of 17 mg of the amino compound and 7.5 g of phthalic anhydride in 1 mL of CHC13 was 6tirred at room temperature for 1 hour. The reaction mixture was concentrated to drynes6 and the residue was triturated with ether. The re~ulting 601id6 were collected and wa6hed with ether. The pure product was obtained as a colorles6 solid, 20 mg, m.p. 150.5-151.5 (dec.).
Example 235 Preparation of 3-t2-Butyl-4-chloro-1-(4-((N-trifluoro-methanesulfonyl)anthranilamido)benzyl)imidazol-5-yl~-propanoic acid methyl e~ter Reaction between the amino compound of Example 234, Part C and o-(trifluoromethanesulfonamido)benzoyl chloride using the conditions described in Example 232 produced the title compound as a 601id, m.p. 168-172.
ExamPle 225 PART A: Preparation of 3-11-(4-Nitrobenzyl)-2-butyl-4-chloroimidazol-S-yl]propanoic acid, N~N-dimethylamide To a 601ution of 0.7 g of propionic acid from Part B of Example 234 in 20 mL of methylene chloride was added 0.5 mL of pyridine, 0.16 q of dimethylamine HCl salt and 0.42 g of dicyclohexylcarbodiimide. The mixture was then stirred at room temperature for 16 hours. At the end of the reaction the mixture was filtered through celite and the filtrate wa6 concen-trated to give a thick oily product. Thus obtained -261 1 3340~2 crude product was purified by fla6h column chroma-tography (100% elution) to give a pure product a~ a thick colorle~s oil, 0.68 g; NMR (200 MHz, CDC13) 2.89 (~, 3H): 2.93 (8, 3H); 5.43 (6, 2H).
PART B: Preparation of 3-tl-(4-AminobenZyl)-2-butyl-4-chloroimidazol-5-yl~propanoic acid, N,N-dimethYlamide T~e nitro compound from Part A wa6 reduced by the 6ame method de6cribed in Part D of ~xample 227 to give the amino compound a6 a 601id, m.p. lq6-148.
PART C: Preparation of 3-12-Butyl-4-chloro-1-(4-((N-trifluoromethane 6ul fonyl)ant~ranilamido)-lS benzyl)imidazol-5-yl]propanoic acid, N,N-dimetbYlamine amide The amino compound from Part B wa6 treated with o-(trifluoromethanesulfonamido)benzoyl chloride a6 de~cribed in Example 232 to give the trifluoromethyl-6ulfonamide product, m.p. 106-108.
- PART D: Preparation of 3-t2-Butyl-4-chloro-1-(4-(2-carboxybenzamido)benzyl)imidazol-5-yl]-propanoic acid, N,N-dimethYlamine amide The amino compound from Part B wa6 reacted with phthalic anhydride a6 de6cribed in Part E of Example 227 to give the phthalamic acid derivative, m.p.
139-lq2 .
262 1 3~4092 Example 237 PART A: Preparation of 3-tl-(4-Nitrobenzyl-2-bUtyl-4-chloroimidazol-5-yl]-2-carboethoxy-2-methylproPanoic acid; ethYl ester A 601ution of 2 g of the malonate derivative obtained from Part A of Example 234 in 10 mL of dried DMF was cooled ~ith ice. To the 601ution was added 0.22 g of Na~ (50% oil disper6ion) and the 601ution was stirred for 5 minutes before adding 0.3 mL of methyl iodide. The reaction mixture then stirred at room temperature for 2 hours. The reaction mixture wa6 diluted with 400 mL of ethyl acetate and the organic layer was wa~hed with H20 and brine. The crude product obtained upon concentration of t~e organic layer was purified by flash 6ilica gel column chromatography (hexane:ethyl acetate=l:l elution) to give a pure compound a6 a thic~ colorles6 oil, 1.8 g.
PART B: Preparation of 3-[1-(4-Nitrobenzyl)-2-butyl-4-chloroimidazol-5-Yl~-2-methylpropanoic acid The malonate derivative from Part A was 6ub-jected to the hydrolysi6-decarboxylation condition as described in Part B of Example 234. The desired compound was obtained as a thic~ yellowish liquid.
PART C: Preparation of 3-tl-(4-Nitrobenzyl)-2-butyl-4-chloroimidazol-5-yl~-2-methylpropanoic acid, isoPropyl ester A mixture of 0.38 g of the acid from Part B, 1 mL of isopropyl alcohol and 0.22 g of dicyclohexyl-carbodiimide in 10 mL of ÇH2C12 was stirred at room temperature for 16 hours. The reaction mixture wa6 concentrated and the re6idue was taken into ethyl acetate. Insoluble material was filtered off and the filtrate was concentrated to give a crude product which -was purified by column chromatography (hexane et~yl acetate=2:1 elution) to give the desired compound as a thick colorle~6 oil, 0.36 q.
PART D: Preparation of 3-tl-(9-((N-trifluoromethane-6ulfonyl)anthranilamido)benzyl)-2-methyl-Propanoic acid, isoPropyl ester Tbe title compound wa6 prepared from tbe e~ter of Part C by the metbod6 described ~n Part6 8 and C of Example 236; m.p. 132-135.
ExamPles 238 and 239 PART A: Preparation of d and 1 3-tl-(4-Nitrobenzyl)-2-butyl-4-cbloroimidazol-5-yl]-2-methyl-proPanoic acid, d-(+)-a-methYlbenzylamide A mixture of 0.71 g of tbe propionic acid derivati~e from Part B of Example 237, 0.25 ~L of d-(+)-a-metbylbenzylamine and 0.4 g of dicyclo~exyl-carbodiimide in 50 mL of CH2C12 wa6 6tirred at room temperature for 16 hours. The reaction mixture was concentrated and residue was di~601ved in 100 mL of etbyl acetate. Insoluble material wa6 filtered off tbrougb Celite and t~e filtrate was concentrated to give a crude product wbich was purified by 6ilica qel column chromatography (hexane:etbyl acetate.2:1 elution). Two dia6tereoisomers were separated as a tbick colorle~s oil, 0.37 q eacb.
PART B: Preparation of d and 1 3-tl-(4-Aminobenzyl) 2-butyl-4-cbloroimidazol-5-yl~-2-metbyl-proPanoic acid, d-(~-a-metbYlben2ylamide Tbe nitro compound from Part A was reduced by the ~ame method de6cribed in Part D of Example 227 to give tbe amino compound a~ a tbick colorle66 oil.
:~`
264 1 3340~2 PART C: Preparation of d and 1 3-tl-(4-(2-Carboxy-benzamido)benzyl-2-butyl-4-chloroimidazol-5-yl]-2-methylpropanoic acid, d-(~)-a-methylbenzYlamide Each dia6teroisomer of the amino compound from Part B wa6 reacted with phthalic anbydride separately as de6cribed in Part E of Example 227, to give the phthalamic acid derivative6, ~.p. 188-189.5 and 201-202, respectiYely.
ExamPle 240 Preparation of 1-[(2'-Carboxybiphenyl-4-yl)methyl~-2-butyl-4-chloroimidazole-5-carboxylic acid - To a ~olution of 1.03 g of 1-t(2'-carbomethoxy-biphenyl-4-yl)methyl~-2-butyl-4-chloro-5-hydroxymethyl-imidazole in 10 mL of anhydrous acetic acid at 25 wa6 added a 601ution of 0.62 ~ of chromium trioxide in 10 mL of water. The mixture wa6 stirred at 25 for 15 minute6 and then poured into water. The precipitated 601ids were recovered by filtration and then di6601ved in 50 mL of 1.0 N aqueous 60dium hydroxide 601ution.
The alkaline 601ution wa6 allowed to 6tand at 25 overnight and then wa6 acidified to pH 3 with 10%
aqueou6 hydrochloric acid. The precipitated 601id was recovered by filtration and recry6tallized from ethyl acetate to afford 0.10 g of 1-t(2~-carboxybiphenyl-4-yl)methyl]-2-butyl-4-chloroimidazole-5-carboxylic acid (m.p. 186-187 (decomp.)). NMR (DMSO-d6) ~ 12.97 (br 6, 2H): 7.68 (d, lH): 7.53 (t, lH): 7.41 (t, lH): 7.34 (d, lH): 7.28 (d, 2H): 7.02 (d, 2H): 5.61 (8, 2H):
2.60 (t, 2H): 1.53 (guint.-, 2H): 1.27 (sext., 2H):
0.81 (t, 3H).
Examples 241-264 were prepared u6ing procedures illustrated in Examples 227-240.
Table 18 ~ 3340~
~7 6 ~r ~ 8 ~ 13 ~o. R6 R~ R8 R13 ~P(-C) 241 n-butyl Cl 2 4-~HCo ~ 115-120 242 n-butyl Cl ~C02CH3 ~-~HC ~ 1~1.5-1~2.5 243 n-butyl Cl ~ CH3 ~-~HC ~ 160-162 H
244 n-butyl Cl (CH2)2COCH3 4-HHC0 ~ 164-162 245 n-propyl Cl CH2CH2C02CH3 4-~HC0 246 n-butyl Cl CH2CH(CH3)C2CH(CH3)2 4-UHC0 ~ 123-125 247 n-butyl Cl (CH2)30~c 4-~HC0 ~ 124-127 Table 18 (continued) 1 3 3 4 0 9 2 Ex.
No. R6 R7 R3 R13 MP(C) 248 n-butyl C1 (CH2)30Ac4-NHC0 ~ 64-67 249 n-butyl C1 CH CH C N ~ 0 4 NHC0 ~ 142-144 250 n-butyl Cl CH2CH2C- ~ 0 4-NHC0 ~ 63-64.5 H
251 n-butyl Cl CH20CNHCH34-NHC0 H0zC
~=N\
N NH (amorpho~s Z5Z n-butyl Cl COzH ~ solid) 253 n-pentyl H C0zH 4 ~
254 n-propyl H CHzCH2C-N ~ 0 4 255 n-propyl Cl `_~CH20H 4 256 n-propyl Cl ~ CHzOH 4 ~r T~hl e 18 (continued) l 3 3 4 0 9 2 No. Bh gl R8 B~ MP (C) 257 n-butyl Cl ~~C~ 4-NHCo~3 258 n-butyl Cl ~CCHz~ 4-NHCo~3 CF3S02Nh 259 n-butyl Cl (cH2)2cNHc6H5 4-NHCO~
CF3SO2Nh 260 n-butyl Cl CH2CH2C-N~N-CH3 4-NHCO~
/~ C~H
261 n-butyl Cl CH2CH2C N~
2 62 n-butyl Cl CH2CH2C-N NH 4-~
CF3S02Nh 263 n-butyl Cl CH2CH2C N N-C6H5 4-~
O CF3so2Nh 2 6 4 n -but y l C l CH2 CH2 C02H )=\ 7 5 - 7 6 . 5 4-Q .D
~?-~-.
. .
268 1 3~40q 2 Table 18 (continued) N R R7 R8 R13 MP(C) -_ _ C02~
265 n-butyl Cl CH2CH2CH2CO2H 4 ~ 83-85 Example 210 PART A: Preparation of 2-(But-l-en-l-yl)-5-t-butyldimethylsilyloxymethyl-l-t(2'-carbo-methoxybiphenyl-4-yl)methyl~-4-chloroimidazole 2-(But-l-en-l-yl)-l-t(2'-carbomethoxybi-phenyl-4-yl)methyl]-4-chloro-5-(hydroxymethyl)-imidazole (1.4 9), t-butyldimethylsilyl chloride (0.55 g), and imidazole (0.5 9) were mixed and 6tirred in DMF (5 mL) for 18 hour6 at room temperature. Dilution with ethyl acetate and washing the organic phase with water followed by drying (MgSO4), evaporation of the solvent in vacuo, and flash chromatography in 3:1 hexane/ethyl acetate yielded 1.5 g of a clear oil. NMR (200 MHz, CDC13) ~ 7.83 (d, lH); 7.52 (t, lH): 7.40 (t, lH);
7.33-7.24 (m, 3H); 7.08 (d, 2H); 6.83 (d of t, lH);
6.13 (d, lH); 5.30 (s, 2H); 4.57 (6, 2H); 3.64 (6, 3H); 2.21 (quint., 2H); 1.04 (t, 3H); 0.86 (s, 9H);
0.05 (s, 6H).
0 PART B: Preparation of 5-t-Butyldimethylsilyloxy-methyl-l-t(2'-carbomethoxybiphenyl-4-yl)-methyl]-4-chloroimidazole-2-carboxaldehyde 2-(But-l-en-l-yl)-5-(t-butyldimethyl6ilyloxy-methyl)-l-[(2-carbomethoxybiphenyl-4-yl)methyl-4-chlorimidazole (262 mg) was reacted with osmium tetroxide and sodium periodate by the procedure described in Example 178, Part B for 1.5 hours at room temperature. Work-up and flash chromatography in 3:1 hexane/ethyl acetate yielded 200 mg of an amorphous 601id. NMR (200 MHz, CDC13) ~ 9.74 (~, lH): 7.84 (d, lH), 7.54 (t, lH), 7.43 (t, lH), 7.34-7.25 (m, 3H), 7.16 (d, 2H) 5.83 (6, 2H), 4.65 (s, 2H), 3.64 (6, 3H), 0.90 (6, 9H), 0.09 (6, 6H).
PART C: Preparation of 5-t-Butyldimethyl6ilyloxy-methyl-l-t(2'-carbomethoxybiphenyl-4-yl)-methyl]-4-chloro-2-(cis-pent-1-en-1-yl)-imidazole 5-t-Butyldimethylsilyloxymethyl-l-t(2'-carbomethoxybiphenyl-4-yl)methyl]-4-chloroimidazole-2-carboxaldehyde (200 mg) was added all at once to a solution of n-butyltriphenylphosphonium bromide (0.26 g) and potassium t-butoxide (70 mg) in THF at 0C.
The reaction mixture was stirred at room temperature for 15 minutes when it was quenched with 6aturated aqueous ammonium chloride solution. The mixture wa~
extracted with ethyl acetate, the organic layer6 washed with water, dried (MgS04) and the 601vent removed ln vacuo. The re~idue was flash chromatographed in hexane/ethyl acetate (5:1) to yield 100 mg of an oil. NMR (200 MHz, CDC13) ~
7.85 (d, lH), 7.54 (t, lH), 7.42 (t, lH), 7.35-7.24 (m, 3H), 7.07 (d, 2H), 6.07 (d, lH), 5.87 (d of t, lH), 5.28 (s, 2H), 4.59 (s, 2H), 3.64 (6, 3H), 2.69 (quart., 2H), 1.46 (sext., 2H), 0.91 (t, 3H), 0.86 (s, 9H), 0.05 (s, 6H).
270 1 3340~2 PART D: Preparation of l-t(2'-Carbomethoxybiphenyl-4-yl)methyl~-4-chloro-5-hydroxymethyl-2-(ci6-pent-l-en-l-yl)imidazole 5-t-Butyldimethyl6ilyloxymethyl-l-~(2'-carbo-methoxybiphenyl-4-yl)methyll-4-chloro-2-(ci6-pent-l-en-l-yl)imidazole (100 mg) wa6 de6ilylated vith fluoride by procedure6 familiar to one 6killed in the art. ~la6h chromatography in 1:1 hexaneJethyl acetate yielded 65 mg of a viscou6, colorle66 oil.
NMR (200 MHz, CDC13) ~ 7.85 (d, lH), 7.55 (t, lH), 7.42 (t, lH), 7.28 (m, 3H), 7.05 (d, ZH), 6.11 (d, lH), 5.92 (d of t, lH), 5.30 (6, 2H), 4.57 (d, 2H), 3.64 (6, 3H), 2.69 (guart., 2H), 1.62 (t, lH), 1.47 (6ext., 2H), 0.92 (t, lH).
PART E: Preparation of l-t(2-Carboxybiphenyl-4-yl)-methyl]-4-chloro-5-hydroxymethyl-2-(ci6-Pent-l-en-l-yl)imidazole l-t2~-Carbomethoxybiphenyl-4-yl)methyl]-4-chloro-5-bydroxymethyl-2-(ci6-pent-l-en-l-yl)-imidazole (65 mg) wa6 hydrolyzed by a procedure 6imilar to that found in ~xample 85, Part E. Work-up yielded 45 mg of colorle66 601id6; m.p. 148-150.
NMR (200 MHz, DMSO-d6) ~ 7.77 (d, lH): 7.50 (t, lH): 7.38 (t, lH): 7.33 (m, 3H): 7.08 (d, 2H): 6.10 (d, lH): 5.84 (d of t, lH): 5.32 (6, 2H): 4.47 (6, 2H): 2.65 (quart., 2H), 1.45 (6ext., 2H): 0.92 (t, 3H).
Table 19 further illu6trate6 compound6 which were made or could be made by the method6 de6cribed in the 6pecification.
Table 19 R6~ N ~R8 (CH2)r ~3 R13 No. E - R R _ ~P(-C) 267 1 n-butyl Cl CH2OH 4 268 1 n-propyl H CH2OH ~ ~
. O
269 1 n-butyl Cl CH2C02CH3 4-NHC ~
270 1 n-pentyl Cl CH2OH 4 ~
o C(CF3)2 271 1 n-butyl Cl CH2NHCOC3H7 4 O
272 2 n-butyl Cl CH20H
273 1 n-propyl H CH20H 4 -Table 19 (continued) 1 3 3 4 0 ~ 2 No. r _ R R R HP('C) 274 1 n-butyl CF3 CH20H 4b NHP-OH
275 1 n-butyl Cl CH20H 4 ~ H
276 1 n-butyl H CH20H ~
276 1 n-hexyl Cl CH2NHC2CH3 4~
OH O
CH-P-OH
278 1 n-butyl ClCH20H 4 279 1 n-butyl ClCH20H 4 N~,NH
280 0 n-butyl ClCH20H
281 1 n-propyl Cl CH20H 4 Table 19 (continue~) 1 3 3 4 0 9 2 _x r R R R R ~P(C) 282 1 n-butyl Cl CH20H 4 ~
C~CO--NHOCH
283 1 n-butyl Cl CH20H 4 ~
284 1 n-hexyl H CH20H 4~C~
Cl ~, 285 1 n-butyl Cl CH20H 4 N=N
N ~ NH
286 1 n-propyl H CH20H
U NH
N=N
N--N~
287 1 n-butyl Cl (CH2)2F 4~
C~
288 1 n-butyl Cl CH20CNHCH3 4-274 1 3340~2 Table 19 (continued) No. r R R _ R Mr( 289 ~ n-butyl Cl CH20CNHCH3 4 ~
C~
290 1 n-propyl H CH2NHCOCH2CH2CH3 4 4 ~ 3 291 1 n-pentyl H CH2NHCNHCH3 ~
292 1 n-butyl ( 2)3 ~ 181-182.5 293 1 n-butyl C1 CH20N02 293 1 n-butyl Cl CH2~ ~ 4 295 1 n-butyl Cl CH20H 4-~(CH3)C0 296 1 n-butyl Cl CH20H 4-CH20 ~
297 1 n-buLyl Cl CH20H 4-SCH
-Table 19 (continucd) 1 3 3 4 0 ~ 2 No. r R R R R MP(C) 298 1 n-butyl Cl CH20H 4-SCH2~3 299 1 n-butyl Cl CH20H 4-COI;H
300 1 n-butyl Cl CH20H 4-NHCH
lS 301 1 n-butyl Cl CH20H 4-N~C ~ 3 20 302 1 n-propyl Cl CH20H 4-S02NH2b 303 1 n-pentyl Cl CH20H 4-CH2NH~3 304 1 n-hexyl Cl CH20H 4-CF=CF ~ ) 305 1 n-butyl Cl CH20H 4-CH=CFb 306 1 n-butyl H CH20H 4- CH2CH
~ 276 Table 19 (continued) l 3 3 4 0 9 2 Ex.
No. r R6 R7 R8 Rl3 MP(C) ~ 2CF3 307 1 n-butyl Cl CH20H 4- ~
308 1 n-butyl Cl CH20H OH
309 1 n-butyl Cl CH20H 4-CH-~
310 1 n-butyl Cl CH20H INOCH3 311 1 n-butyl Cl CH20H 4-C ~
CF3SO2'N
H
312 1 n-propyl H CH20H 4-C ----- ~
313 1 n-pentyl Cl CH20H O /O
314 1 n-butyl Cl CH=CHCH20H 4 ~ 103-104.5 ~, Utility 277 I 3340~2 The hormone angiotensin II (AII) produce6 numerous biological responses (e.g. va60con~triction) through stimulation of its receptor6 on cell membranes.
For the purpo~e of identifying compound6 6uch a6 AII
antagoni~t6 which are capable of interacting with the AII receptor, a ligand-receptor binding a66ay wa6 utilized for the initial ~creen. T~e a66ay wa6 carried out according to the method de6cribed by tGl066mann et al., J. Biol. Chem., 249, 825 (1974)], but with 60me modifications. The reaction ~ixture contained rat adrenal cortical micro60me6 (60urce of AII receptor) in Tri6 buffer and 2 nM of H-AII with or without potential AII antagoni~t. T~is mixture wa6 incubated for 1 hour at room temperature and the reaction wa6 6ub6equently terminated by rapid filtration and rin6ing through gla66 micro-fibre filter. Receptor-bound 3H-AII trapped in filter wa6 quantitated by 6cintillation counting. The inhibitory concentration (IC50) of potential AII antagoni6t which give6 50%
di6placement of the total 6pecifically bound H-AII
i6 pre6ented a6 a mea6ure of the affinity of 6uch compound for the AII receptor (6ee Table 20).
The potential antihyperten6ive effect6 of the compounds of this invention may be demonstrated by admini6tering the compounds to awake rat6 made hyperten6ive by ligation of the left renal artery ~Cangiano et al., J. Pharmacol. Exp. Ther., 208, 310 (1979)~. Thi6 procedure increa6e6 blood pre66ure by increasing renin production with consequent elevation of AII level6. Compounds are admini6tered orally at 100 mg~kg a~d~or intca~enou61y via a cannula in the jugular vein at 10 mg/kg. Arterial blood pre66ure is continuously mea6ured directly through a carotid artery cannula and recorded using a pres6ure -278 1 3340~2 transducer and a polygraph. Blood pres6ure level6 after treatment are compared to pretreatment level6 to determine the antihyperten6ive effect6 of t~e compounds (See Table 20).
Table 20 Angioten6in II Antihyperten6ive Receptor Effect6 in Renal Bindinq HYperten6ive Rat6 IC50 Intravenou6 Oral Ex. No. (~molar) ActivitYl Activity2 1 1.80 + NA
2 (60dium ~alt) 0.140 + NA
3 (60dium 6alt) 0.420 NA
4 (60dium 6alt) 0.280 + NA
5 (60dium 6alt) 0.190 NA
6 5.70 NT
7 0.420 + NA
8 (60dium 6alt) 0.790 NA
9 (60dium 6alt) 5.80 NT
10 (60dium 6alt) 0.190 NT
11 (60dium 6alt) 0.380 NA NA
12 (60dium 6alt) 0.030 + NA
13 (sodium 6alt) 6.90 + NA
14 3.20 NT
15 (60dium 6alt) 9.4 + NA
16 0.018 + NA
17 (60dium 6alt) 0.042 + NA
18 0.08 + NA
19 (60dium 6alt) 1.70 NT
20 (60dium 6alt) 5.30 NT
21 (60dium 6alt) 2.10 + NA
3.90 NT
26 (60dium 6alt) 3.80 NA
27 (60dium 6alt) 1.20 + +
Table 20 (continued) I 3 ~40~2 Angiotensin II Antihypertensive Receptor Effects in Renal Bindinq HYPertensive Rats IC50 Intravenous Oral Ex. ~o. (~molar~ ActivitY Activity 28 8.00 NT
29 3.10 ~ NA
30 (sodium 6alt) 0.39 + +
31 0.64 NT
32 (sodium salt) 0.43 NT
33 0.940 NT
35 (sodium salt) 3.40 + +
36 (sodium salt) 0.19 + NA
51 2.30 NA NA
52 1.10 NT
54 7.20 +
0.930 + NA
56 4.40 NT
57 4.90 + NA
58 8.30 + NA
59 3.00 NA NA
1.20 NT
61 5.00 NT
62 (sodium salt) 9.20 NT
63 (sodium salt) 3.70 NA
64 0.620 + NA
0.240 + NA
66 0.350 + NA
67 1.10 + NA
2.50 + NA
71 2.80 NT
72 6.50 + NA
280 I 3 340q2 Table 20 (continued) Angiotensin II Anti~yperten6ive Receptor Effect6 in Renal Bindinq Hyperten6ive Rat6 IC50 Intravenou6 Oral Ex. No. (~molar) ActivitY ActivitY
74 (tran6 compound) 3.90 + NA
(ci6 compound) 4.50 + NA
75 (60dium 6alt) 7.60 + +
76 (60dium 6alt) 2.70 + NA
77 (60dium 6alt) 5.70 NA NA
78 (60dium 6alt) 8.00 + +
79 (60dium 6alt) 0.50 + NA
80 (60dium 6alt) 0.50 + +
81 (60dium ~alt) 0.57 NA NA
82 6.10 NT
83 6.40 NT
0.49 + +
86 2.90 + NA
87 2.50 NT
88 1.30 +
89 0.039 + +
90 (60dium 6alt) 0.020 + +
91 0.26 + NA
92 0.062 +
93 0.89 + NA
94 0.2BO + +
1.20 + NA
96 1.10 NT
97 0.270 + NA
98 (60dium 6alt) 0.099 + +
-TabIe 20 (continued) 1 3340~2 Angioten5in II Antihyperten6ive Receptor Pffect6 in Renal Bindinq HYperten6ive Rat6 IC50 Intravenouc Oral Ex. No. (~molar) ActivitY Activity gg o.oso ~ ~
100 0.090 ~ +
102 0.061 +
105 0.680 + +
106 1.90 107 1.70 NT
108 0.160 ~ +
109 0.98 + +
110 1.30 + +
113 0.020 NT
114 0.050 + +
116 0.26 + +
117 0.89 + +
118 0.089 +
121 0.330 + +
123 5.60 + NA
124 1.80 + NA
125 0.650 + +
126 0.340 + +
127 0.150 + +
128 0.08 + +
129 0.330 +
130 0.470 +
132 0.020 +
134 0.180 +
135 1.30 + +
141 0.190 + +
282 1 ~340~2 Table 20 (continued) Angioten~in II Antihyperten6ive Receptor Effect6 in Renal Bindinq HyPerten6ive Rat6 IC50 Intravenou6 Oral Ex. No. (~molar) ActivitY Activity 144 0.083 + +
148 (60dium 6alt) 0.200 ~ +
149 (60dium 6alt) 0.450 + +
150 (60dium 6alt) 0.200 + +
151 (60dium 6alt) 0.560 + +
152 (60dium 6alt) 0.250 + +
153 (60dium 6alt) 0.200 +
154 (60dium 6alt) 0.60 +
156 0.060 +
160 (60dium salt) 0.120 + +
162 (60dium 6alt) 0.140 + +
165 (60dium 6alt) 3.00 + NA
166 (60dium 6alt) 0.240 + NA
171 (60dium 6alt) 0.600 + NA
173 (60dium 6alt) 0.700 +
174 (sodium 6alt) 0.300 + NA
175 (DCHA 6alt) 1.50 + NA
176 0.200 + NA
177 9.60 + NA
178 4.20 + +
179 4.40 + NA
180 2.90 + NA
181 4.90 + NA
182 4.10 + NA
183 6.30 + NA
184 0.40 + NA
Table 20 (continued) 1 3 3 4 0 9 2 Angiotensin II Antihyperten~ive Receptor Effect6 in Renal Bindinq HYperten6ive Rat6 IC50 Intravenou6 Oral Ex. No. (~molar) ActivitYl Activity2 185 0.400 + NA
192 2.30 NA
193 0.31 + NA
194 1.20 NT
195 0.92 +
199 1.80 NA
202 (60dium 6alt) 0.160 + NA
203 (60dium 6alt) 0.340 + +
204 (60dium 6alt) 1.90 + NA
205 (60dium 6alt) 2.50 NT
206 (60dium salt) 1.40 NT
207 (sodium 6alt) 0.15 + +
208 (60dium 6alt) 0.330 + NA
209 (60dium 6alt) 0.27 NT
215 (60dium 6alt) 0.200 + NA
217 (60dium 6alt) 2.70 NT
218 (60dium 6alt) 2.0 NT
219 0.68 NT
223 5.40 NT
224 5.90 NT
227 0.110 +
228 0.530 NT
229 2.10 + +
230 1.60 +
231 0.0i6 NT
232 0.510 +
Table 20 (continued) 1 334092 Angiotensin II Antihypertensive Receptor Effect6 in Renal Bindinq HYPerten6ive Rat6 IC50 Intravenou6 Oral Ex. No. (umolar) ActivitYl Activity 233 0.600 + +
234 0.064 + NA
235 0.160 + NA
236 0.110 +
237 0.120 + NA
238 0.110 + NA
239 0.092 +
241 0.170 +
242 0.270 +
243 0.200 NT
244 0.088 +
246 0.120 +
247 0.110 NT
248 0.250 +
249 0.072 + NA
250 0.120 + NA
264 0.250 + +
265 0.270 + +
266 2.30 +
292 0.700 + +
314 0.630 + NA
1 Significant decrease in blood pre~sure at 10 mg/kg or less 2 Significant decrea6e in blood pressure at 100 mg/kg or le~6 NA - Not active at 100 mg/kg dosage admini6tered.
Although many of the compound~ te6ted were not active orally, they were active intravenously. A few compound6 (Example6 10, 51, ~9, 77 and 81~ did not produce a significant decrea6e in blood pre66ure at 10 mg/kg intravenou61y, but did produce some decrease at that level, and it i6 expected that they would be active intravenously at a ~ig~er dosage, e.g., 30 mg/kg.
NT - Not te6ted.
286 1 3340~2 DosaPe Forms The compounds of thls invention can be adminlstered for the treatment of hypertension according to the invention by any means that effects contact of the.active in8redient cc _-~nd S with the site of action in the body of a warm-blooded animal.
For example, administration can be parenteral, i.o., subcutaneous, ~ntr~venous, ~nt,- -~ lPr, or lntra peritoneal.
~lternatively, or concurrently, in ~ome cases admini~tration can be by the oral route.
The compounds can be admlnistered by any conventional means avallable for use in con~unction with pharmaceutlcals, elther as individual theiapeutic agents or ln a combination of therapeutic asents. They can be a~ ln~stered alone, but are ~enerally adminlstered with a pharmaceutlcal carrier ~elected on the basis of the chosen route of -' ;n~stration and standard pharmaceutical practice.
For the purpose of this disclosure, a warm-blooded animal is a member of the animal kingdom possessed of a homeostatic mechanism and includes - -ls and birds.
Ihe dosage administered will be dependent on the age, health and weight of the recipient, the extent of disease, kind of concurrent treatment, ~f any, f~eque~cy of treatment and the nature of the effect desired. Usually, a daily dosage of active in8redient compound will be from about 1-500 milli~rams per day. Ordinarily, from 10 to 100 milligrams per day in one or more applications ls effective to obtain deslred results.
These dosages are the effective amounts both for treatment of hn ertension and for tretment of con~estive heart fallure, i.e., for lowering blood pressure nd for correcting the hemodynamic burden on the heart to relleve the congestion.
The actlve in~redient can be ~ inistered orally in solid dosage forms, such as capsules, tablets, and powders, or in liquid dosa~e forms, such as elixirs ~yrups, and ~uspensions.
It can also be administered parenterally, in sterile liquid dosa~e forms.
287 1 3340~2 Gelatin capsules contain the active ingredient and powdered carriers, 6uch as lactose, starch, cellulo6e derivatives, magne6ium 6tearate, 6tearic acid, and the like. Similar diluent6 can be u6ed to make compres6ed tablet6. ~oth tablet6 and cap6ule6 can be manufactured a~ 6u~tained release products to provide for continuou6 release of ~edication over a period of hour6. Compre6sed tablet6 can be sugar coated or film coated to ma6~ any unplea6ant taste and protect t~e tablet from the atmo6phere, or enteric coated for selective di6integration in the gastro-inte6tinal tract.
~ iquid do6age form6 for oral admini6tration can contain coloring and flavoring to increa6e patient acceptance.
In general, water, a 6uitable oil, 6aline, aqueou6 dextro6e (gluco6e), and related sugar 601ution6 and glycol6 6uch a6 propylene glycol or polyethylene glycol6 are 6uitable carriers for parenteral solution6. Solutions for parenteral admini6tration preferably contain a water soluble 6alt of the active ingredient, suitable 6tabilizing agents, and if nece66ary, buffer 6ub6tance6. Antioxidizing agent6 such a6 sodium bi6ulfite, sodium sulfite, or a6corbic acid, either alone or combined, are suitable 6tabilizing agent6. Al60 u6ed are citric acid and it6 salt6 and sodium EDTA. In addition, parenteral solu-tion6 can contain pre6ervative6, such a6 benzal~onium c~loride, ~ethyl- or propylparaben, and chlorobutanol.
Suitable p~armaceutical carrier6 are de6cribed in Reminqton's Pharmaceutical Science~, A. Ocol, a standard reference text in this field.
Useful pharmaceutical do6age-forms for admini-6tration of the compound6 of thi6 invention can be illu~trated as follows:
-288 ~ 33409~
CaPsules A large number of unit capsules are prepared by filling 6tandard two-piece hard gelatin cap6ule~ each wit~ 100 milligrams of powdered active ingredient, 150 milligrams of lacto6e, 50 milligrams of cellulose, and 6 milligrams magne6ium stearate.
Soft Gelatin Capsule6 A mixture of actiYe ingredient in a dige6tible oil suc~ as soybean oil, cotton6eed oil or olive oil is prepared and injected by means of a positive di6placement pump into gelatin to form soft gelatin cap~ules containing 100 milligrams of the active ingredient. T~e cap6ule6 are wached and dried.
Tablet6 A large number of tablets are prepared by conventional procedure~ 60 t~at the dosage unit is 100 mill~gra~ of active ingredient, 0.2 milligrams of colloidal silicon dioxide, 5 milligram6 of magnesium 6tearate, 275 milligrams of microcrystalline cellulose, 11 milligrams of starc~ and 98.8 milligrams of lactose.
Appropriate coating6 may be applied to increase palat-ability or delay ab~orption.
Iniectable A parenteral composition suitable for administration by injection is prepared by stirring 1.5~ by weig~t of active ingredient in 10% by volume propylene glycol. T~e solution i6 made to volume with ~ater for injection and sterilized.
Su6pension An aqueou~ suspension i6 prepared for oral adminictration 80 that eac~ 5 milliliter6 contain 100 milligrams of finely divided active i~gre~ient, 100 milligrams of sodiu~ carboxymet~yl cellulose, 5 milligrams of 60dium benzoate, 1.0 grams of sorbitol 601ution, U.S.P., and 0.025 milliliters of vanillin.
3.90 NT
26 (60dium 6alt) 3.80 NA
27 (60dium 6alt) 1.20 + +
Table 20 (continued) I 3 ~40~2 Angiotensin II Antihypertensive Receptor Effects in Renal Bindinq HYPertensive Rats IC50 Intravenous Oral Ex. ~o. (~molar~ ActivitY Activity 28 8.00 NT
29 3.10 ~ NA
30 (sodium 6alt) 0.39 + +
31 0.64 NT
32 (sodium salt) 0.43 NT
33 0.940 NT
35 (sodium salt) 3.40 + +
36 (sodium salt) 0.19 + NA
51 2.30 NA NA
52 1.10 NT
54 7.20 +
0.930 + NA
56 4.40 NT
57 4.90 + NA
58 8.30 + NA
59 3.00 NA NA
1.20 NT
61 5.00 NT
62 (sodium salt) 9.20 NT
63 (sodium salt) 3.70 NA
64 0.620 + NA
0.240 + NA
66 0.350 + NA
67 1.10 + NA
2.50 + NA
71 2.80 NT
72 6.50 + NA
280 I 3 340q2 Table 20 (continued) Angiotensin II Anti~yperten6ive Receptor Effect6 in Renal Bindinq Hyperten6ive Rat6 IC50 Intravenou6 Oral Ex. No. (~molar) ActivitY ActivitY
74 (tran6 compound) 3.90 + NA
(ci6 compound) 4.50 + NA
75 (60dium 6alt) 7.60 + +
76 (60dium 6alt) 2.70 + NA
77 (60dium 6alt) 5.70 NA NA
78 (60dium 6alt) 8.00 + +
79 (60dium 6alt) 0.50 + NA
80 (60dium 6alt) 0.50 + +
81 (60dium ~alt) 0.57 NA NA
82 6.10 NT
83 6.40 NT
0.49 + +
86 2.90 + NA
87 2.50 NT
88 1.30 +
89 0.039 + +
90 (60dium 6alt) 0.020 + +
91 0.26 + NA
92 0.062 +
93 0.89 + NA
94 0.2BO + +
1.20 + NA
96 1.10 NT
97 0.270 + NA
98 (60dium 6alt) 0.099 + +
-TabIe 20 (continued) 1 3340~2 Angioten5in II Antihyperten6ive Receptor Pffect6 in Renal Bindinq HYperten6ive Rat6 IC50 Intravenouc Oral Ex. No. (~molar) ActivitY Activity gg o.oso ~ ~
100 0.090 ~ +
102 0.061 +
105 0.680 + +
106 1.90 107 1.70 NT
108 0.160 ~ +
109 0.98 + +
110 1.30 + +
113 0.020 NT
114 0.050 + +
116 0.26 + +
117 0.89 + +
118 0.089 +
121 0.330 + +
123 5.60 + NA
124 1.80 + NA
125 0.650 + +
126 0.340 + +
127 0.150 + +
128 0.08 + +
129 0.330 +
130 0.470 +
132 0.020 +
134 0.180 +
135 1.30 + +
141 0.190 + +
282 1 ~340~2 Table 20 (continued) Angioten~in II Antihyperten6ive Receptor Effect6 in Renal Bindinq HyPerten6ive Rat6 IC50 Intravenou6 Oral Ex. No. (~molar) ActivitY Activity 144 0.083 + +
148 (60dium 6alt) 0.200 ~ +
149 (60dium 6alt) 0.450 + +
150 (60dium 6alt) 0.200 + +
151 (60dium 6alt) 0.560 + +
152 (60dium 6alt) 0.250 + +
153 (60dium 6alt) 0.200 +
154 (60dium 6alt) 0.60 +
156 0.060 +
160 (60dium salt) 0.120 + +
162 (60dium 6alt) 0.140 + +
165 (60dium 6alt) 3.00 + NA
166 (60dium 6alt) 0.240 + NA
171 (60dium 6alt) 0.600 + NA
173 (60dium 6alt) 0.700 +
174 (sodium 6alt) 0.300 + NA
175 (DCHA 6alt) 1.50 + NA
176 0.200 + NA
177 9.60 + NA
178 4.20 + +
179 4.40 + NA
180 2.90 + NA
181 4.90 + NA
182 4.10 + NA
183 6.30 + NA
184 0.40 + NA
Table 20 (continued) 1 3 3 4 0 9 2 Angiotensin II Antihyperten~ive Receptor Effect6 in Renal Bindinq HYperten6ive Rat6 IC50 Intravenou6 Oral Ex. No. (~molar) ActivitYl Activity2 185 0.400 + NA
192 2.30 NA
193 0.31 + NA
194 1.20 NT
195 0.92 +
199 1.80 NA
202 (60dium 6alt) 0.160 + NA
203 (60dium 6alt) 0.340 + +
204 (60dium 6alt) 1.90 + NA
205 (60dium 6alt) 2.50 NT
206 (60dium salt) 1.40 NT
207 (sodium 6alt) 0.15 + +
208 (60dium 6alt) 0.330 + NA
209 (60dium 6alt) 0.27 NT
215 (60dium 6alt) 0.200 + NA
217 (60dium 6alt) 2.70 NT
218 (60dium 6alt) 2.0 NT
219 0.68 NT
223 5.40 NT
224 5.90 NT
227 0.110 +
228 0.530 NT
229 2.10 + +
230 1.60 +
231 0.0i6 NT
232 0.510 +
Table 20 (continued) 1 334092 Angiotensin II Antihypertensive Receptor Effect6 in Renal Bindinq HYPerten6ive Rat6 IC50 Intravenou6 Oral Ex. No. (umolar) ActivitYl Activity 233 0.600 + +
234 0.064 + NA
235 0.160 + NA
236 0.110 +
237 0.120 + NA
238 0.110 + NA
239 0.092 +
241 0.170 +
242 0.270 +
243 0.200 NT
244 0.088 +
246 0.120 +
247 0.110 NT
248 0.250 +
249 0.072 + NA
250 0.120 + NA
264 0.250 + +
265 0.270 + +
266 2.30 +
292 0.700 + +
314 0.630 + NA
1 Significant decrease in blood pre~sure at 10 mg/kg or less 2 Significant decrea6e in blood pressure at 100 mg/kg or le~6 NA - Not active at 100 mg/kg dosage admini6tered.
Although many of the compound~ te6ted were not active orally, they were active intravenously. A few compound6 (Example6 10, 51, ~9, 77 and 81~ did not produce a significant decrea6e in blood pre66ure at 10 mg/kg intravenou61y, but did produce some decrease at that level, and it i6 expected that they would be active intravenously at a ~ig~er dosage, e.g., 30 mg/kg.
NT - Not te6ted.
286 1 3340~2 DosaPe Forms The compounds of thls invention can be adminlstered for the treatment of hypertension according to the invention by any means that effects contact of the.active in8redient cc _-~nd S with the site of action in the body of a warm-blooded animal.
For example, administration can be parenteral, i.o., subcutaneous, ~ntr~venous, ~nt,- -~ lPr, or lntra peritoneal.
~lternatively, or concurrently, in ~ome cases admini~tration can be by the oral route.
The compounds can be admlnistered by any conventional means avallable for use in con~unction with pharmaceutlcals, elther as individual theiapeutic agents or ln a combination of therapeutic asents. They can be a~ ln~stered alone, but are ~enerally adminlstered with a pharmaceutlcal carrier ~elected on the basis of the chosen route of -' ;n~stration and standard pharmaceutical practice.
For the purpose of this disclosure, a warm-blooded animal is a member of the animal kingdom possessed of a homeostatic mechanism and includes - -ls and birds.
Ihe dosage administered will be dependent on the age, health and weight of the recipient, the extent of disease, kind of concurrent treatment, ~f any, f~eque~cy of treatment and the nature of the effect desired. Usually, a daily dosage of active in8redient compound will be from about 1-500 milli~rams per day. Ordinarily, from 10 to 100 milligrams per day in one or more applications ls effective to obtain deslred results.
These dosages are the effective amounts both for treatment of hn ertension and for tretment of con~estive heart fallure, i.e., for lowering blood pressure nd for correcting the hemodynamic burden on the heart to relleve the congestion.
The actlve in~redient can be ~ inistered orally in solid dosage forms, such as capsules, tablets, and powders, or in liquid dosa~e forms, such as elixirs ~yrups, and ~uspensions.
It can also be administered parenterally, in sterile liquid dosa~e forms.
287 1 3340~2 Gelatin capsules contain the active ingredient and powdered carriers, 6uch as lactose, starch, cellulo6e derivatives, magne6ium 6tearate, 6tearic acid, and the like. Similar diluent6 can be u6ed to make compres6ed tablet6. ~oth tablet6 and cap6ule6 can be manufactured a~ 6u~tained release products to provide for continuou6 release of ~edication over a period of hour6. Compre6sed tablet6 can be sugar coated or film coated to ma6~ any unplea6ant taste and protect t~e tablet from the atmo6phere, or enteric coated for selective di6integration in the gastro-inte6tinal tract.
~ iquid do6age form6 for oral admini6tration can contain coloring and flavoring to increa6e patient acceptance.
In general, water, a 6uitable oil, 6aline, aqueou6 dextro6e (gluco6e), and related sugar 601ution6 and glycol6 6uch a6 propylene glycol or polyethylene glycol6 are 6uitable carriers for parenteral solution6. Solutions for parenteral admini6tration preferably contain a water soluble 6alt of the active ingredient, suitable 6tabilizing agents, and if nece66ary, buffer 6ub6tance6. Antioxidizing agent6 such a6 sodium bi6ulfite, sodium sulfite, or a6corbic acid, either alone or combined, are suitable 6tabilizing agent6. Al60 u6ed are citric acid and it6 salt6 and sodium EDTA. In addition, parenteral solu-tion6 can contain pre6ervative6, such a6 benzal~onium c~loride, ~ethyl- or propylparaben, and chlorobutanol.
Suitable p~armaceutical carrier6 are de6cribed in Reminqton's Pharmaceutical Science~, A. Ocol, a standard reference text in this field.
Useful pharmaceutical do6age-forms for admini-6tration of the compound6 of thi6 invention can be illu~trated as follows:
-288 ~ 33409~
CaPsules A large number of unit capsules are prepared by filling 6tandard two-piece hard gelatin cap6ule~ each wit~ 100 milligrams of powdered active ingredient, 150 milligrams of lacto6e, 50 milligrams of cellulose, and 6 milligrams magne6ium stearate.
Soft Gelatin Capsule6 A mixture of actiYe ingredient in a dige6tible oil suc~ as soybean oil, cotton6eed oil or olive oil is prepared and injected by means of a positive di6placement pump into gelatin to form soft gelatin cap~ules containing 100 milligrams of the active ingredient. T~e cap6ule6 are wached and dried.
Tablet6 A large number of tablets are prepared by conventional procedure~ 60 t~at the dosage unit is 100 mill~gra~ of active ingredient, 0.2 milligrams of colloidal silicon dioxide, 5 milligram6 of magnesium 6tearate, 275 milligrams of microcrystalline cellulose, 11 milligrams of starc~ and 98.8 milligrams of lactose.
Appropriate coating6 may be applied to increase palat-ability or delay ab~orption.
Iniectable A parenteral composition suitable for administration by injection is prepared by stirring 1.5~ by weig~t of active ingredient in 10% by volume propylene glycol. T~e solution i6 made to volume with ~ater for injection and sterilized.
Su6pension An aqueou~ suspension i6 prepared for oral adminictration 80 that eac~ 5 milliliter6 contain 100 milligrams of finely divided active i~gre~ient, 100 milligrams of sodiu~ carboxymet~yl cellulose, 5 milligrams of 60dium benzoate, 1.0 grams of sorbitol 601ution, U.S.P., and 0.025 milliliters of vanillin.
Claims (60)
1. An antihypertensive compound of the formula:
(I) wherein R1 is -4-CO2H; -4-CO2R9; ; -SO3H;
-C(CF3)2OH; ; - PO3H; ;
4-NHSO2CH3; 4-NHSO2CF3; -CONHOR12;
- SO2NH2; ; ;
; ; ;
; ; ;
; 4-CONHNHSO2CF3; (/ isomer) (/ isomer); ; ;
; ; R2 is H; Cl; Br; I; F; NO2; CN; alkyl of 1 to 4 carbon atoms; acyloxy of 1 to 4 carbon atoms; alkoxy of 1 to 4 carbon atoms; CO2H; CO2R9; NHSO2CF3; NHSO2CH3;
CONHOR12; SO2NH2; ; phenyl; or furyl R3 is H, Cl, Br, I or F; alkyl of 1 to 4 carbon atoms or alkoxy of 1 to 4 carbon atoms;
R4 is CN, NO2 OR CO2R11;
R5 is H, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, alkenyl or alkynyl of 2 to 4 carbon atoms;
R6 is alkyl of 2 to 10 carbon atoms, alkenyl or alkynyl of 3 to 10 carbon atoms or the same groups substituted with F or CO2R14: cycloalkyl of 3 to 8 carbon atoms, cycloalkylalkyl, of 4 to 10 carbon atoms; cycloalkylalkenyl or cycloalkylalkynyl of 5 to 10 carbon atoms;
(CH2)sZ(CH2)mR5; (CH2),sZ(CH2) mR5; substituted with F or CO2R14; benzyl or benzyl substituted on the phenyl ring with 1 or 2 halogens, alkoxy of 1 to 4 carbon atoms, alkyl of 1 to 4 carbon atoms or nitro;
R7 is H, F, Cl, Br, I, NO2, CF3 or CN;
R8 is H, CN, alkyl of 1 to 10 carbon atoms, alkenyl of 3 to 10 carbon atoms, or the same groups substituted with F; phenylalkenyl wherein the aliphatic portion is 2 to 6 carbon atoms;
-(CH2)m-imidazol-l-yl; -(CH2)m-1,2,3-triazolyl;
-(CH2)m-1,2,3-triazolyl substituted with one or two groups selected from CO2CH3 or alkyl of 1 to 4 carbon atoms; -(CH2)m-tetrazolyl;
-(CH2)nOR11; ; -(CH2)nSR15;
; ; ;
;
; ; ;
; ; ;
; -(CH2)mF ; -(CH2)mONO2 ; -CH2N3;
(CH2)mNO2; ;
R9 is ;
R10 is alkyl of 1 to 6 carbon atoms or perfluoro-alkyl of 1 to 6 carbon atoms, 1-adamantyl, 1-naphthyl, 1-(1-naphthyl)ethyl, or (CH2)pC6H5;
R11 is H, alkyl of 1 to 6 carbon atoms, cyclo-alkyl of 3 to 6 carbon atoms, phenyl or benzyl;
R12 is H, methyl or benzyl;
R13 is -CO2H; -CO2R9: -CH2CO2H, -CH2CO2R9:
; ; -SO3H; -PO3H2; -C(CF3)2OH; -NHSO2CH3; -NHSO2CF3; -NHCOCF3;
-CONHOR12; -SO2NH2; ; ;
; ; -CONHNHSO2CF3;
; or ;
R14 is H, alkyl or perfluoroalkyl of 1 to 8 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, phenyl or benzyl;
R15 is H, alkyl of 1 to 6 carbon atoms, cyclo-alkyl of 3 to 6 carbon atoms, phenyl, benzyl, acyl of 1 to 4 carbon atoms, phenyl carbonyl, R16 is H, alkyl of 1 to 6 carbon atoms, cyclo-alkyl of 3 to 6 carbon atoms, (CH2)pC6H5, OR17, or NR18R19;
R17 is H, alkyl of 1 to 6 carbon atoms, cyclo-alkyl of 3 to 6 carbon atoms, phenyl or benzyl;
R18 and R19 independently are H, alkyl of 1 to 4 carbon atoms, phenyl, benzyl, .alpha.-methylbenzyl, or taken together with a nitrogen atom form a ring of the formula ;
Q is NR20, O or CH2;
R20 is H, alkyl of 1-4 carbon atoms, or phenyl;
R21 is alkyl of 1 to 6 carbon atoms, -NR22R23, or ;
R22 and R23 independently are H, alkyl of 1 to 6 carbon atoms, benzyl, or are taken together as (CH2)u where u is 3-6;
R24 is H, CH3 or -C6H5;
R25 is NR27R28, OR28, NHCONH2, NHCSNH2, or ;
R26 is hydrogen, alkyl with from 1 to 6 carbon atoms, benzyl, or allyl;
R27 and R28 are independently hydrogen, alkyl with from 1 to 5 carbon atoms, or phenyl;
R29 and R30 are independently alkyl of 1-4 carbon atoms or taken together are -(CH2)q-;
R31 is H, alkyl of 1 to 4 carbon atoms, -CH2CH=CH2 or -CH2C6H4R32;
R32 is H, NO2, NH2, OH or OCH3;
X is a carbon-carbon single bond, -CO-. -O-, -S-, -NH-, , , , -OCH2-, -CH2O-, -SCH2-, -CH2S-, -NHC(R27)(R28), -NR23SO2-, -SO2NR23-,-C(R27)(R28)NH-, -CH=CH-, -CF=CF-, -CH=CF-, -CF=CH-, -CH2CH2-, -CF2CF2-, , , , , or ;
Y is O or S;
Z is O, NR11 or S;
m is 1 to 5;
n is 1 to 10;
p is 0 to 3;
q is 2 to 3;
r is 0 to 2;
s is 0 to 5;
t is 0 or 1;
and pharmaceutically acceptable salts of these compounds;
provided that:
(1) the R1 group is not in the ortho position (2) when R1 is , X is a single bond, and R13 is CO2H, or , then R13 must be in the ortho or meta position; or when R1 and X are as above and R13 is NHSO2CF3 or NHSO2CH3, R13 must be ortho;
(3) when R1 is , and X is other than a single bond, then R13 must be ortho except when X = NR23CO and R13 is NHSO2CF3 or NHSO2CH3, then R13 must be ortho or meta;
(4) when R1 is 4-CO2H or a salt thereof, R6 cannot be S-alkyl;
(5) when R1 is 4-CO2H or a salt thereof, the substituent on the 4-position of the imidazole cannot be CH2OH, CH2OCOCH3, or CH2CO2H;
(6) when R1 is . X is -OCH2-, R13 is 2-CO2H, and R7 is H then R6 is not C2H5S;
(7) when R1 is , and R6 is n-hexyl then R7 and R8 are not both hydrogen;
(8) when R1 is , R6 is not methoxy-benzyl;
(9) the R6 group is not or CH2OH; and (10) when r=0, then R' is not 4-NHSO2CH3 or 4-NHSO2CF3.
(I) wherein R1 is -4-CO2H; -4-CO2R9; ; -SO3H;
-C(CF3)2OH; ; - PO3H; ;
4-NHSO2CH3; 4-NHSO2CF3; -CONHOR12;
- SO2NH2; ; ;
; ; ;
; ; ;
; 4-CONHNHSO2CF3; (/ isomer) (/ isomer); ; ;
; ; R2 is H; Cl; Br; I; F; NO2; CN; alkyl of 1 to 4 carbon atoms; acyloxy of 1 to 4 carbon atoms; alkoxy of 1 to 4 carbon atoms; CO2H; CO2R9; NHSO2CF3; NHSO2CH3;
CONHOR12; SO2NH2; ; phenyl; or furyl R3 is H, Cl, Br, I or F; alkyl of 1 to 4 carbon atoms or alkoxy of 1 to 4 carbon atoms;
R4 is CN, NO2 OR CO2R11;
R5 is H, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, alkenyl or alkynyl of 2 to 4 carbon atoms;
R6 is alkyl of 2 to 10 carbon atoms, alkenyl or alkynyl of 3 to 10 carbon atoms or the same groups substituted with F or CO2R14: cycloalkyl of 3 to 8 carbon atoms, cycloalkylalkyl, of 4 to 10 carbon atoms; cycloalkylalkenyl or cycloalkylalkynyl of 5 to 10 carbon atoms;
(CH2)sZ(CH2)mR5; (CH2),sZ(CH2) mR5; substituted with F or CO2R14; benzyl or benzyl substituted on the phenyl ring with 1 or 2 halogens, alkoxy of 1 to 4 carbon atoms, alkyl of 1 to 4 carbon atoms or nitro;
R7 is H, F, Cl, Br, I, NO2, CF3 or CN;
R8 is H, CN, alkyl of 1 to 10 carbon atoms, alkenyl of 3 to 10 carbon atoms, or the same groups substituted with F; phenylalkenyl wherein the aliphatic portion is 2 to 6 carbon atoms;
-(CH2)m-imidazol-l-yl; -(CH2)m-1,2,3-triazolyl;
-(CH2)m-1,2,3-triazolyl substituted with one or two groups selected from CO2CH3 or alkyl of 1 to 4 carbon atoms; -(CH2)m-tetrazolyl;
-(CH2)nOR11; ; -(CH2)nSR15;
; ; ;
;
; ; ;
; ; ;
; -(CH2)mF ; -(CH2)mONO2 ; -CH2N3;
(CH2)mNO2; ;
R9 is ;
R10 is alkyl of 1 to 6 carbon atoms or perfluoro-alkyl of 1 to 6 carbon atoms, 1-adamantyl, 1-naphthyl, 1-(1-naphthyl)ethyl, or (CH2)pC6H5;
R11 is H, alkyl of 1 to 6 carbon atoms, cyclo-alkyl of 3 to 6 carbon atoms, phenyl or benzyl;
R12 is H, methyl or benzyl;
R13 is -CO2H; -CO2R9: -CH2CO2H, -CH2CO2R9:
; ; -SO3H; -PO3H2; -C(CF3)2OH; -NHSO2CH3; -NHSO2CF3; -NHCOCF3;
-CONHOR12; -SO2NH2; ; ;
; ; -CONHNHSO2CF3;
; or ;
R14 is H, alkyl or perfluoroalkyl of 1 to 8 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, phenyl or benzyl;
R15 is H, alkyl of 1 to 6 carbon atoms, cyclo-alkyl of 3 to 6 carbon atoms, phenyl, benzyl, acyl of 1 to 4 carbon atoms, phenyl carbonyl, R16 is H, alkyl of 1 to 6 carbon atoms, cyclo-alkyl of 3 to 6 carbon atoms, (CH2)pC6H5, OR17, or NR18R19;
R17 is H, alkyl of 1 to 6 carbon atoms, cyclo-alkyl of 3 to 6 carbon atoms, phenyl or benzyl;
R18 and R19 independently are H, alkyl of 1 to 4 carbon atoms, phenyl, benzyl, .alpha.-methylbenzyl, or taken together with a nitrogen atom form a ring of the formula ;
Q is NR20, O or CH2;
R20 is H, alkyl of 1-4 carbon atoms, or phenyl;
R21 is alkyl of 1 to 6 carbon atoms, -NR22R23, or ;
R22 and R23 independently are H, alkyl of 1 to 6 carbon atoms, benzyl, or are taken together as (CH2)u where u is 3-6;
R24 is H, CH3 or -C6H5;
R25 is NR27R28, OR28, NHCONH2, NHCSNH2, or ;
R26 is hydrogen, alkyl with from 1 to 6 carbon atoms, benzyl, or allyl;
R27 and R28 are independently hydrogen, alkyl with from 1 to 5 carbon atoms, or phenyl;
R29 and R30 are independently alkyl of 1-4 carbon atoms or taken together are -(CH2)q-;
R31 is H, alkyl of 1 to 4 carbon atoms, -CH2CH=CH2 or -CH2C6H4R32;
R32 is H, NO2, NH2, OH or OCH3;
X is a carbon-carbon single bond, -CO-. -O-, -S-, -NH-, , , , -OCH2-, -CH2O-, -SCH2-, -CH2S-, -NHC(R27)(R28), -NR23SO2-, -SO2NR23-,-C(R27)(R28)NH-, -CH=CH-, -CF=CF-, -CH=CF-, -CF=CH-, -CH2CH2-, -CF2CF2-, , , , , or ;
Y is O or S;
Z is O, NR11 or S;
m is 1 to 5;
n is 1 to 10;
p is 0 to 3;
q is 2 to 3;
r is 0 to 2;
s is 0 to 5;
t is 0 or 1;
and pharmaceutically acceptable salts of these compounds;
provided that:
(1) the R1 group is not in the ortho position (2) when R1 is , X is a single bond, and R13 is CO2H, or , then R13 must be in the ortho or meta position; or when R1 and X are as above and R13 is NHSO2CF3 or NHSO2CH3, R13 must be ortho;
(3) when R1 is , and X is other than a single bond, then R13 must be ortho except when X = NR23CO and R13 is NHSO2CF3 or NHSO2CH3, then R13 must be ortho or meta;
(4) when R1 is 4-CO2H or a salt thereof, R6 cannot be S-alkyl;
(5) when R1 is 4-CO2H or a salt thereof, the substituent on the 4-position of the imidazole cannot be CH2OH, CH2OCOCH3, or CH2CO2H;
(6) when R1 is . X is -OCH2-, R13 is 2-CO2H, and R7 is H then R6 is not C2H5S;
(7) when R1 is , and R6 is n-hexyl then R7 and R8 are not both hydrogen;
(8) when R1 is , R6 is not methoxy-benzyl;
(9) the R6 group is not or CH2OH; and (10) when r=0, then R' is not 4-NHSO2CH3 or 4-NHSO2CF3.
2. A compound of claim 1 having the formula:
(II) Wherein R1 is -CO2H; -NHSO2CF3; ; ;
or ;
R6 is alkyl of 3 to 10 carbon atoms, alkenyl of
(II) Wherein R1 is -CO2H; -NHSO2CF3; ; ;
or ;
R6 is alkyl of 3 to 10 carbon atoms, alkenyl of
3 to 10 carbon atoms, alkynyl of 3 to 10 carbon atoms, cycloalkyl of 3 to 8 carbon atoms, benzyl substituted on the phenyl ring with up to two groups selected from alkoxy of 1 to 4 carbon atoms, halogen, alkyl of 1 to 4 carbon atoms, and nitro;
R8 is phenylalkenyl wherein the aliphatic portion is 2 to 4 carbon atoms, -(CH2)m-imidazol-1-yl, -(CH2)m-1,2,3-triazolyl optionally substi-tuted with one or two groups selected from CO2CH3 or alkyl of 1 to 4 carbon atoms, (CH2)m-tetrazolyl, -(CH2)nOR11 ; ;
, ;
; ; -(CH2)nNHSO2R10;
;
R13 is -CO2H, -CO2R9, NHSO2CF3; and ;
R16 is H, alkyl of 1 to 5 carbon atoms, OR17, or NR18R19;
X is carbon-carbon single bond, -CO-, , -CH2CH2-, ' -OCH2-. -CH2O-, -O-, -SCH2-, -CH2S-, -NHCH2-, -CH2NH- or -CH=CH-; and pharmaceutically acceptable salts of these compounds.
3. A compound of claim 2 wherein:
R2 is H, alkyl of 1 to 4 carbon atoms, halogen, or alkoxy of 1 to 4 carbon atoms;
R6 is alkyl, alkenyl or alkynyl of 3 to 7 carbon atoms;
R7 is H, Cl, Br, I or CF3;
R8 is -(CH2)mOR11; ; ;
; ;
-(CH2)mNHSO2R10; ; or -COR16;
R10 is CF3, alkyl of 1 to 6 carbon atoms or phenyl;
R11 is H, or alkyl of 1 to 4 carbon atoms;
R13 is CO2H; CO2CH2OCOC(CH3)3; NHSO2CF3 and ;
R14 is H, or alkyl of 1 to 4 carbon atoms;
R15 is H, alkyl of 1 to 4 carbon atoms, or acyl of 1 to 4 carbon atoms;
R16 is H, alkyl of 1 to 5 carbon atoms; OR17; or ;
m is 1 to 5;
X = single bond, -O-; -CO-; -NHCO-; or -OCH2-; and pharmaceutically acceptable salts.
R8 is phenylalkenyl wherein the aliphatic portion is 2 to 4 carbon atoms, -(CH2)m-imidazol-1-yl, -(CH2)m-1,2,3-triazolyl optionally substi-tuted with one or two groups selected from CO2CH3 or alkyl of 1 to 4 carbon atoms, (CH2)m-tetrazolyl, -(CH2)nOR11 ; ;
, ;
; ; -(CH2)nNHSO2R10;
;
R13 is -CO2H, -CO2R9, NHSO2CF3; and ;
R16 is H, alkyl of 1 to 5 carbon atoms, OR17, or NR18R19;
X is carbon-carbon single bond, -CO-, , -CH2CH2-, ' -OCH2-. -CH2O-, -O-, -SCH2-, -CH2S-, -NHCH2-, -CH2NH- or -CH=CH-; and pharmaceutically acceptable salts of these compounds.
3. A compound of claim 2 wherein:
R2 is H, alkyl of 1 to 4 carbon atoms, halogen, or alkoxy of 1 to 4 carbon atoms;
R6 is alkyl, alkenyl or alkynyl of 3 to 7 carbon atoms;
R7 is H, Cl, Br, I or CF3;
R8 is -(CH2)mOR11; ; ;
; ;
-(CH2)mNHSO2R10; ; or -COR16;
R10 is CF3, alkyl of 1 to 6 carbon atoms or phenyl;
R11 is H, or alkyl of 1 to 4 carbon atoms;
R13 is CO2H; CO2CH2OCOC(CH3)3; NHSO2CF3 and ;
R14 is H, or alkyl of 1 to 4 carbon atoms;
R15 is H, alkyl of 1 to 4 carbon atoms, or acyl of 1 to 4 carbon atoms;
R16 is H, alkyl of 1 to 5 carbon atoms; OR17; or ;
m is 1 to 5;
X = single bond, -O-; -CO-; -NHCO-; or -OCH2-; and pharmaceutically acceptable salts.
4. The compound of claim 3, 2-Butyl-4-chloro-1-[(2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]-5-(hydroxymethyl)imidazole, or a pharmaceutically acceptable salt thereof.
5. The compound of claim 3, 2-Butyl-4-chloro-1-[(2'-carboxybiphenyl-4-yl)methyl]-5-(hydroxymethyl)-imidazole, or a pharmaceutically acceptable salt thereof.
6. The compound of claim 3, 2-Butyl-4-chloro-1-[(2'-carboxybiphenyl-4-yl)methyl]-5-[(methoxycarbonyl)-aminomethyl]imidazole, or a pharmaceutically acceptable salt thereof.
7. The compound of claim 3, 2-Butyl-4-chloro-1-[(2'-carboxybiphenyl-4-yl)methyl]-5-[(propoxycarbonyl)-aminomethyl]imidazole, or a pharmaceutically acceptable salt thereof.
8. The compound of claim 3, 2-Butyl-4-chloro-1-[(2'-carboxybiphenyl-4-yl)methyl]imidazole-5-carboxaldehyde, or a pharmaceutically acceptable salt thereof.
9. The compound of claim 3, 2-Butyl-1-[(2'-carboxybiphenyl-4-yl)methyl]imidazole-5-carboxaldehyde, or a pharmaceutically acceptable salt thereof.
10. The compound of claim 3, 2-(1E-Butenyl)-4-chloro-1-[(2'-carboxybiphenyl-4-yl)methyl]-5-(hydroxymethyl)imidazole, or a pharmaceutically acceptable salt thereof.
11. The compound of claim 3, 2-(1E-Butenyl)-4-chloro-1-[(2'-carboxybiphenyl-4-yl)methyl] imidazole-5-carboxaldehyde, or a pharmaceutically acceptable salt thereof.
12. The compound of claim 3, 2-propyl-4-chloro-1-[2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]-5-(hydroxymethyl)imidazole, or a pharmaceutically acceptable salt thereof.
13. The compound of claim 3, 2-propyl-4-chloro-1-[2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]imidazole-5-carboxaldehyde, or a pharmaceutically acceptable salt thereof.
14. The compound of claim 3, 2-butyl-4-chloro-1-[2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]imidazole-5-carboxaldehyde, or a pharmaceutically acceptable salt thereof.
15. The compound of claim 3, 2-(1E-butenyl)-4-chloro-1-[(2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]-5-(hydroxymethyl)imidazole, or a pharmaceutically acceptable salt thereof.
16. The compound of claim 3, 2-(1E-butenyl)-4-chloro-1-[(2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]-imidazole-5-carboxaldehyde, or a pharmaceutically acceptable salt thereof.
17. A pharmaceutical composition comprising a pharmaceutically suitable carrier and an antihypertensive compound of claim 1, 2 or 3.
18. A process for the preparation of a compound of claim 1 wherein r is 1 which comprises contacting an imidazole derivative of Formula 1 with a benzyl derivative of Formula 2 in a solvent in the presence of a base for about 1 to about 10 hours at a temperature in the range of about 20°C to the reflux temperature of the solvent to form a benzylimidazole of Formula 3:
+ wherein each of R1, R2, R3, R6, R7 and R8 is stable under the reaction conditions and is a group as defined in claim 1 or an intermediate or protected form thereof which can be transformed to such a group and wherein X1 is halogen, p-toluenesulfonyloxy or methylsulfonyloxy; and thereafter as necessary transforming said intermediate or protected forms of the R groups to R groups as defined in claim 1.
+ wherein each of R1, R2, R3, R6, R7 and R8 is stable under the reaction conditions and is a group as defined in claim 1 or an intermediate or protected form thereof which can be transformed to such a group and wherein X1 is halogen, p-toluenesulfonyloxy or methylsulfonyloxy; and thereafter as necessary transforming said intermediate or protected forms of the R groups to R groups as defined in claim 1.
19. Process of claim 18 wherein compounds 1 and 2 are contacted in the presence of a base selected from the group consisting of a metal hydride, MH, a metal alkoxide, MOR, sodium carbonate, potassium carbonate, triethylamine and pyridine, in a dipolar aprotic solvent or, where the base is MOR, the solvent can be an alcohol, ROH, where M is lithium, sodium or potassium and R is methyl, ethyl or t-butyl.
20. Process of claim 18 wherein: R1 is ; ; or ;
X is a carbon-carbon single bond, -CO-, -O-, -S-, or -NH-;
R2 and R3 are each independently H, Cl, Br, I, CO2R14, F, NO2, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, aryl or furyl;
R6 and R7 are as defined in claim 18;
R8 is alkyl of 1 to 10 carbon atoms or alkenyl of 3 to 10 carbon atoms, or the same groups substituted with F;
phenylalkenyl wherein the aliphatic portion is 2 to 6 carbon atoms; -(CH2)nOR11;
-(CH2)nSR15; or -(CH2)nCN;
R11 is as defined in Claim 18;
R13 is CO2R14, CN, NO2, trialkyltin tetrazole, or trityltetrazole; and R14 and R15 are as defined in Claim 18.
X is a carbon-carbon single bond, -CO-, -O-, -S-, or -NH-;
R2 and R3 are each independently H, Cl, Br, I, CO2R14, F, NO2, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, aryl or furyl;
R6 and R7 are as defined in claim 18;
R8 is alkyl of 1 to 10 carbon atoms or alkenyl of 3 to 10 carbon atoms, or the same groups substituted with F;
phenylalkenyl wherein the aliphatic portion is 2 to 6 carbon atoms; -(CH2)nOR11;
-(CH2)nSR15; or -(CH2)nCN;
R11 is as defined in Claim 18;
R13 is CO2R14, CN, NO2, trialkyltin tetrazole, or trityltetrazole; and R14 and R15 are as defined in Claim 18.
21. Process of Claim 20 wherein R13 is -CO2R14 and the product of Formula 3 is contacted with an alkali in an aqueous alcoholic solvent or with CF3CO2H at a temperature in the range of about 20°C to the reflux temperature of the solvent for about 1-24 hours, followed by adjustment of the pH of the mixture to a value in the range of 3 to 7, to convert the product to the corresponding product wherein R13 is -CO2H.
22. Process of Claim 21 wherein at least one of R2, R3 or R13 in Formula 1 is -CO2R14 and is converted to -CO2H.
23. Process of Claim 21 wherein R14 is t-butyl and the reaction is conducted in CF3CO2H.
24. Process of Claim 20 wherein R13 is -CN
and the product of Formula 3 is contacted with (i) a strong acid at reflux temperature of the solvent for about 2-96 hours or (ii) a strong alkali in an alcohol solvent at a temperature in the range of about 20°C and the reflux temperature of the solvent for about 2-96 hours followed by adjustment of the pH
to about 3-7, or (iii) sulfuric acid followed by acid or alkali, to convert the product to the corresponding compound wherein R13 is -CO2H.
and the product of Formula 3 is contacted with (i) a strong acid at reflux temperature of the solvent for about 2-96 hours or (ii) a strong alkali in an alcohol solvent at a temperature in the range of about 20°C and the reflux temperature of the solvent for about 2-96 hours followed by adjustment of the pH
to about 3-7, or (iii) sulfuric acid followed by acid or alkali, to convert the product to the corresponding compound wherein R13 is -CO2H.
25. Process of Claim 24 wherein at least one of R2, R3 or R13 is -CO2R14 and is converted to -CO2H.
26. Process of Claim 24 wherein R8 is -(CH2)nCN and is converted to -(CH2)nCO2H, or is -(CH2)nOR11 and is converted to (CH2)nOH when R13 is converted to -CO2H.
27. Process of Claim 20 wherein R13 is -CN
and the product of Formula 3 is contacted with a mixture of equimolar amounts of sodium azide and ammonium chloride in a polar aprotic solvent at a temperature in the range of about 30°C to the reflux temperature of the solvent, for about 1 hour to 10 days, to convert the product to the corresponding compound wherein R13 is 5-tetrazolyl.
and the product of Formula 3 is contacted with a mixture of equimolar amounts of sodium azide and ammonium chloride in a polar aprotic solvent at a temperature in the range of about 30°C to the reflux temperature of the solvent, for about 1 hour to 10 days, to convert the product to the corresponding compound wherein R13 is 5-tetrazolyl.
28. Process of Claim 27 wherein R8 is -(CH2)CN and is converted to -(CH2)m-tetrazolyl when R13 is converted to 5-tetrazolyl.
29. Method of Claim 20 wherein R13 is -CN
and the product of Formula 3 is reacted with trialkyltin azide or triaryltin azide followed by acidic or basic hydrolysis to convert the product to the corresponding compound wherein R13 is 5-tetrazolyl.
and the product of Formula 3 is reacted with trialkyltin azide or triaryltin azide followed by acidic or basic hydrolysis to convert the product to the corresponding compound wherein R13 is 5-tetrazolyl.
30. Process of Claim 29 wherein R8 is -(CH2)nCN and is converted to -(CH2)m-tetrazolyl when R13 is converted to 5-tetrazolyl.
31. Process of Claim 20 wherein R13 is -NO2 and the product of Formula 3 is contacted with a reducing agent to form a second intermediate of Formula 3 in which R13 is NH2, and the latter is contacted with an anhydride (CH3SO2)2O or (CF3SO2)2O or a chloride CH3SO2C1 or CF3SO2C1 of sulfonic acid in a solvent to produce a compound in which R13 is -NHSO2CH3 or -NHSO2CF3.
32. Process of Claim 31 wherein at least one of R2, R3, or R13 is -NO2 and is converted to -NHSO2CH3 or -NHSO2CF3.
33. Process of Claim 21 or 24 wherein the compound of Formula 3 with R13=CO2H either (a) is contacted with about 1-4 equivalents of thionyl chloride in excess thionyl chloride or another solvent at a temperature in the range of about 20°C to the reflux temperature of the solvent for a period of about 5 minutes to about 2 hours to form an intermediate of Formula 3 wherein R13 is COCl, and the latter is contacted with about 2-10 equivalents of hydroxylamine derivative H2NOR12 in excess hydroxylamine derivative H2NOR12 or other solvent, at a temperature in the range of about 25-80°C for about 2-18 hours, or (b) is contacted the hydroxylamine derivative H2NOR12, dicyclohexylcarbodiimide and 1-hydroxybenzotriazole in a solvent at a temperature in the range of about 0-30°C for about 1-24 hours:
to provide a compound in which R13 is CONHOR12.
to provide a compound in which R13 is CONHOR12.
34. Process of claim 18 wherein: R1 is ; ; or ;
X is a carbon-carbon single bond, -CO-, -O-, -S-, or -NH-;
R2, R3, R6 and R7 are as defined in claim 18;
and R8 is (CH2)nOR11, (CH2)nOCOR14, (CH2)nCH(OH)R16, (CH2)nCOR16 (CH2)nCl, (CH2)nCN, CHO.
X is a carbon-carbon single bond, -CO-, -O-, -S-, or -NH-;
R2, R3, R6 and R7 are as defined in claim 18;
and R8 is (CH2)nOR11, (CH2)nOCOR14, (CH2)nCH(OH)R16, (CH2)nCOR16 (CH2)nCl, (CH2)nCN, CHO.
35. Process of claim 34 wherein R8 is (CH2)nOH and the product of Formula 3 is contacted with an alcohol R11OH in the anhydrous state in the presence of a strong acid or a Lewis acid, followed by saponification of any CO2R14 groups concomitantly formed or present in intermediate 3, to form the corresponding compound of Formula 3 wherein R8 is (CH2)nOR11 and R11 is not H.
36. Process of claim 34 wherein R8 is (CH2)nOR11 and R11 is not H and the product of Formula 3 is contacted with an aqueous acidic medium at a temperature in the range of about 25°C and the reflux temperature of the solvent for a period of about 0.5-24 hours to form the corresponding compound of Formula 3 wherein R8 is (CH2)nOH.
37. Process of Claim 34 wherein R8 is (CH2)nOH and the product of Formula 3 is contacted with (a) a carboxylic acid anhydride (R14CO)2O or chloride R14COCl in a solvent in presence of a base at a temperature in the range of about 0°C and the reflux temperature of the solvent for about 0.5-24 hours or (b) a carboxylic acid R14CO2H under anhydrous conditions in presence of a strong acid or Lewis acid at about 0°-100°C for about 0.5 to 24 hours, to form the corresponding compound in which R8 is (CH2)nOCOR14.
38. Process of Claim 34 wherein R8 is (CH2)nOCOR14 and the product of Formula 3 is contacted with aqueous acid or alkali to form the corresponding compound wherein R8 is (CH2)nOH.
39. Process of Claim 34 wherein R8 is (CH2)nOH and the product of Formula 3 is contacted with an oxidizing agent at a temperature of about 25-45°C for about 1-200 hours to produce a corresponding compound of Formula 3 in which R8 is (CH2)n-1COR16 and R16 is H.
40. Process of Claim 34 wherein R8 is (CH2)nCOR16 and R16 is H and the product of Formula 3 is contacted with an organometallic compound R16P in which P is MgBr or Li in a solvent at a temperature in the range of about -78°C to 100°C
for about 0.5-24 hours to form a compound of Formula 3 in which R8 is (CH2)nCH(OH)R16 and R16 is not H.
for about 0.5-24 hours to form a compound of Formula 3 in which R8 is (CH2)nCH(OH)R16 and R16 is not H.
41. Process of Claim 34 wherein R8 is (CH2)nCH(OH)R16 and R16 is not H and the product of Formula 3 is contacted with an oxidizing agent in a solvent to form a corresponding compound of Formula 3 in which R8 is (CH2)nCOR16 and R16 is not H.
42. Process of Claim 34 wherein R8 is (CH2)nCOR16 and R16 is H and the compound of Formula 3 is contacted with an oxidizing agent in a solvent to form a corresponding compound of Formula 3 in which R8 is (CH2)nCOR16 and R16 is OH.
43. Process of Claim 34 wherein R8 is (CH2)nCOR16 and R16 is OH and the compound of Formula 3 is contacted with thionyl chloride in excess or in another solvent at a temperature in the range of about 0°C to the reflux temperature of the solvent for about 5 minutes to about 24 hours to form a corresponding compound of Formula 3 in which R8 is (CH2)nCOCl followed by contact of the latter with an amine NHR18R19 in excess or in a solvent at temperatures in the range of about 0°C and reflux temperature of the solvent for about 5 minutes to about 24 hours to form a corresponding compound of Formula 3 in which R8 is (CH2)nCONR18R19.
44. Process of Claim 34 wherein R8 is (CH2)nOR11 and R11 is H and the product of Formula 3 is contacted with thionyl chloride in excess or in a solvent at a temperature in the range of about 20°C to the reflux temperature of the solvent for about 0.5-24 hours to form an intermediate compound of Formula 3 in which R8 is (CH2)nCl.
45. Process of Claim 44 in which the compound of Formula 3 wherein R8 is (CH2)mCl is contacted with imidazole, 1,2,3-triazole, 1,2,4-triazole, tetrazole or phthalimide in the presence of base in a solvent at temperatures in the range of about 55°C to the reflux temperature of the solvent for about 1-24 hours to produce a corresponding compound of Formula 3 in which R8 is (CH2)m-imidazole, (CH2)m-triazole, (CH2)m-tetrazole or (CH2)m-phthalimide.
46. Process of Claim 44 wherein the compound of Formula 3 in which R8 is (CH2)nCl is contacted with sodium or potassium salt of a mercaptan R15SH in a solvent at a temperature in the range of about 25-100°C for about 1-24 hours to form a compound of Formula 3 in which R8 is (CH2)nSR15.
47. Process of Claim 34 wherein the compound of Formula 3 in which R8 is (CH2)nCl is contacted with an alkali metal cyanide in a solvent at a temperature in the range of about 20-100°C for about 1-24 hours to form a compound of Formula 3 in which R8 is (CH2)nCN and the latter compound is hydrolyzed to the corresponding compound of Formula 3 in which R8 is (CH2)nCOR16 and R16 is OH.
48. Process of Claim 34 wherein the compound of Formula 3 in which R8 is (CH2)n-lCl is contacted with the sodium or potassium salt of a dialkyl malonate in a solvent at a temperature in the range of about 20-100°C for about 0.5-24 hours to form a compound of Formula 3 in which R8 is (CH2)nCH(CO2alkyl)2 followed by saponification of the latter with aqueous alkali at a temperature in the range of about 25°C to the reflux temperature of the solvent followed by acidification with mineral acid to form a compound of Formula 3 in which R8 is (CH2)nCH(CO2H)2 followed by heating the latter to about 120°C or in dilute mineral acid at reflux temperature to form a product of Formula 3 in which R8 is (CH2)nCOR16 and R16 is OH.
49. Process of Claim 34 wherein R8 is (CH2)nCN and the compound of Formula 3 is contacted with sodium azide and ammonium chloride in a solvent at a temperature in the range of about 30°C
and the reflux temperature of the solvent for about 1 hour to about 10 days to form a compound of the invention in which R8 is (CH2)n-tetrazole.
and the reflux temperature of the solvent for about 1 hour to about 10 days to form a compound of the invention in which R8 is (CH2)n-tetrazole.
50. Process of Claim 34 wherein R8 is -CHO
and the compound of Formula 3 is contacted with a methylene phosphorane (C6H5)3P=CH(CH2)sCHR14OR15 or (C6H5)3P=CH(CH2)sCOR16 in a solvent at a temperature in the range of about 25°C to the reflux temperature of the solvent for about 1-24 hours to form a compound of Formula 3 in which R8 is -CH=CH(CH2)sCHR14OR15 or -CH=CH(CH2)sCOR16, except where R15 is H and R16 is OH, and optionally then contacting the compound of Formula 3 in which R8 is -CH=CH(CH2)sCOR16 with a reducing agent in a solvent at a temperature of about 0°-25°C for about 0.5-24 hours to form a product of Formula 3 in which R8 is -CH=CH(CH2)sCHR14OH.
and the compound of Formula 3 is contacted with a methylene phosphorane (C6H5)3P=CH(CH2)sCHR14OR15 or (C6H5)3P=CH(CH2)sCOR16 in a solvent at a temperature in the range of about 25°C to the reflux temperature of the solvent for about 1-24 hours to form a compound of Formula 3 in which R8 is -CH=CH(CH2)sCHR14OR15 or -CH=CH(CH2)sCOR16, except where R15 is H and R16 is OH, and optionally then contacting the compound of Formula 3 in which R8 is -CH=CH(CH2)sCOR16 with a reducing agent in a solvent at a temperature of about 0°-25°C for about 0.5-24 hours to form a product of Formula 3 in which R8 is -CH=CH(CH2)sCHR14OH.
51. Process of Claim 34 wherein R8 is (CH2)mOH and the compound of Formula 3 is contacted with a fluorinating agent in a solvent at a temperature in the range of about -30°C to 25°C for a period of about 0.5-24 hours to form a compound of Formula 3 in which R8 is (CH2)mF.
52. Process of Claim 34 wherein the compound of Formula 3 in which R8 is (CH2)mCl is contacted with silver nitrate in a dipolar aprotic solvent at a temperature in the range of about 25-80°C for about 1-24 hours to form a compound of Formula 3 in which R8 is (CH2)mONO2.
53. Process of Claim 34 wherein R8 is (CH2)nOH and the compound of Formula 3 is contacted with an isocyanate of Formula R10NCO in a solvent at a temperature in the range of about 25°C
to the reflux temperature of the solvent for a period of about 5 minutes to about 24 hours to form a compound of Formula 3 in which R8 is (CH2)nOCONHR10.
to the reflux temperature of the solvent for a period of about 5 minutes to about 24 hours to form a compound of Formula 3 in which R8 is (CH2)nOCONHR10.
54. Process of Claim 34 wherein the compound in which R8 is (CH2)nCl is contacted with an amine R11NH2 in excess amine or another solvent for a period of about 1-24 hours at a temperature in the range of about 0°C to the reflux temperature of the solvent to form an intermediate of Formula 3 in which R8 is (CH2)nNHR11.
55. Process of Claim 34 in which R8 is (CH2)nCl and the compound of Formula 3 is contacted with an alkali metal azide in an aprotic solvent at a temperature in the range of about 25-80°C for about 1-24 hours to form a compound of Formula 3 in which R8 is (CH2)nN3 and the latter is contacted with a reducing agent to form an intermediate of Formula 3 in which R8 is (CH2)nNH2.
56. Process of Claim 54 or 55 in which R8 is (CH2)nNHR11 or (CH2)nNH2 and the compound of Formula 3 is contacted with a chloroformate of Formula R10OCOCl or a sulfonyl derivative of Formula R10SO2Cl, or (R10SO2)O in a solvent in the presence of a base at a temperature in the range of about 0°C to the reflux temperature of a solvent for about 5 minutes to about 24 hours to form a compound of Formula 3 in which R8 is -(CH2)nNR11CO2R10 or -(CH2)nNR11SO2R10.
57. Process of Claim 54 or 55 in which the compound of Formula 3 with R8 equal to -(CH2)nNHR11 or (CH2)nNH2 is contacted with an isocyanate or isothiocyanate R10NCY in a solvent at a temperature in the range of about 25°C
to the reflux temperature of the solvent for about 5 minutes to about 24 hours to form a compound of the Formula 3 in which R8 is -(CH2)nNR11CYNHR10.
to the reflux temperature of the solvent for about 5 minutes to about 24 hours to form a compound of the Formula 3 in which R8 is -(CH2)nNR11CYNHR10.
58. Process of Claim 18 wherein R1 is NO2 R2, R3, R6, R7, and R8 are as defined in Claim 18 in which the compound of Formula 3 wherein R1 is NO2 is reduced by means of iron and acetic acid, stannous chloride or hydrogen and palladium to a compound of Formula 3 wherein R1 is NH2 and the latter is reacted with an appropriate acid anhydride such as phthalic anhydride or a substituted phthalic anhydride in a solvent or with an appropriate acid chloride such as substituted anthranilic acid chloride in the presence of aqueous alkali or a base or with an appropriately substituted phthalic or anthranilic acid in the presence of dicyclohexyl-carbodiimide in a solvent to produce a compound of the Formula 3 in which R1 is ; ; or ;
and X is NHCO.
and X is NHCO.
59. Process of Claim 18 wherein R1 is OCH2C6H5, R2 and R3 are H and R6, R7, and R8 are as defined in Claim 18 and the resulting compound of Formula 3 with R1 equal to OCH2C6H5 is contacted with trifluoroacetic acid at reflux temperature for a period of about 0.2-1 hour or with hydrogen and palladium to form the corresponding compound of Formula 3 in which R1 is OH and the latter is contacted with a base at about 25°C and a suitable benzyl halide of the formula:
; ; or to produce the corresponding compound of Formula 3 wherein R1 is ; ; or ;
and X is -OCH2-.
; ; or to produce the corresponding compound of Formula 3 wherein R1 is ; ; or ;
and X is -OCH2-.
60. Method of claim 18 wherein R8 is -CHO, whereby the benzyl derivative of Formula 2 attaches to the imidazole derivative of Formula 1 preferentially at the nitrogen atom adjacent the carbon atom of the imidazole ring to which R8 is attached.
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US88492086A | 1986-07-11 | 1986-07-11 | |
| US884,920 | 1986-07-11 | ||
| US5034187A | 1987-05-22 | 1987-05-22 | |
| US050,341 | 1987-05-22 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1334092C true CA1334092C (en) | 1995-01-24 |
Family
ID=26728162
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000540399A Expired - Lifetime CA1334092C (en) | 1986-07-11 | 1987-06-23 | Angiotensin ii receptor blocking imidazoles |
Country Status (20)
| Country | Link |
|---|---|
| EP (1) | EP0253310B1 (en) |
| KR (2) | KR900005020B1 (en) |
| AT (1) | ATE113276T1 (en) |
| AU (1) | AU599396B2 (en) |
| CA (1) | CA1334092C (en) |
| CY (1) | CY1855A (en) |
| DE (2) | DE19675001I2 (en) |
| DK (1) | DK174700B1 (en) |
| ES (1) | ES2063734T4 (en) |
| FI (1) | FI96025C (en) |
| HK (1) | HK55495A (en) |
| HU (2) | HU218460B (en) |
| IE (1) | IE69984B1 (en) |
| IL (1) | IL83153A (en) |
| LU (1) | LU88662I2 (en) |
| LV (1) | LV5486A3 (en) |
| NL (1) | NL950009I2 (en) |
| NO (2) | NO176049C (en) |
| PT (1) | PT85312B (en) |
| SU (1) | SU1694062A3 (en) |
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- 1987-07-10 AU AU75596/87A patent/AU599396B2/en not_active Expired
- 1987-07-10 PT PT85312A patent/PT85312B/en unknown
- 1987-07-10 DK DK198703596A patent/DK174700B1/en not_active IP Right Cessation
- 1987-07-11 KR KR1019870007464A patent/KR900005020B1/en not_active IP Right Cessation
-
1990
- 1990-02-23 KR KR1019900002283A patent/KR900005045B1/en not_active IP Right Cessation
-
1993
- 1993-05-14 LV LV930351A patent/LV5486A3/en unknown
-
1995
- 1995-04-11 HK HK55495A patent/HK55495A/en not_active IP Right Cessation
- 1995-05-26 NO NO1995004C patent/NO1995004I1/en unknown
- 1995-06-07 NL NL950009C patent/NL950009I2/en unknown
-
1996
- 1996-04-05 CY CY185596A patent/CY1855A/en unknown
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