NZ234841A - Intermediates for preparing antifungal carbinols - Google Patents

Intermediates for preparing antifungal carbinols

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NZ234841A
NZ234841A NZ23484187A NZ23484187A NZ234841A NZ 234841 A NZ234841 A NZ 234841A NZ 23484187 A NZ23484187 A NZ 23484187A NZ 23484187 A NZ23484187 A NZ 23484187A NZ 234841 A NZ234841 A NZ 234841A
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pyridyl
thienyl
carbon atoms
alkyl
formula
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NZ23484187A
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John Cuomo
Richard Scot Greenberg
Richard Eric Olson
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Du Pont
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Priority claimed from NZ220798A external-priority patent/NZ220798A/en
Publication of NZ234841A publication Critical patent/NZ234841A/en

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New Zealand Paient Spedficaiion for Paient Number £34841 •„ .V a*.J i"'-V ♦ Priority Dalo(:tf: . k?'.
Compleio Specification Filed: *&-., C-fp^.^a/o sti Sf?3, ozia£* ^ithliraSnn noto. '7 NOV 1990 ::\53E:::::::: Publication Date: P.O. Journal. No ■% -gss Cent: 71 / ■ ~^.w222»/.lf=i KX\&^ I Q 'o / 'I!.-.r.r. (>••:: Vr<=>. /J.QhlL ... ! - c Patents Form No. 5 234 84 1 Under the provisions of Regulation 23 (1) the CRfcvplf&r.
Specification has been ante-dated to X3..3iX& 19 ??..., Initials This is a divisional out of application 220798 of 22 June 1987 NEW ZEALAND PATENTS ACT 1953 COMPLETE SPECIFICATION INTERMEDIATES IN THE PREPARATION OF ANTIFUNGAL CARBINOLS WE, E.I. DU PONT DE NEMOURS AND COMPANY, a corporation organised and existing under the laws of the State of Delaware, of 10th and Market Streets, Wilmington, Delaware, United States of America, hereby declare the invention, for which we pray that a patent may be granted to us, and the method by which it is to be performed, to be particularly described in and by the following statement: la 234 84 1 This invention relates to compounds which are intermediates in the preparation of antifungal carbinols, particularly o<-styryl carbinols, and the corresponding fpoxy carbinols. The invention also provides processes for preparing the intermediates.
Systemic fungal infections are of increasing importance because of continued and expanded use of immunosuppressive therapies, antimicrobial therapies and indwelling catheters. Currently there are limited therapies available to treat such fungal infections. Amphotericin B remains the drug of choice because it has the widest spectrum of antifungal activity of any systemic antifungal drug, however its utility is limited by its toxicity. Because of the potential seriousness of its toxic effects, intravenous use of amphotericin B is primarily for patients with progressive, potentially fatal infections in which the patient is hospitalized during the course of therapy. Thus, there is a continuing need to develop safer and more effective drugs which are useful for the treatment of fungal infections. la (followed by page 2) i, 234 8 2 Plant pathogenic fungi and other disease incitants also cause extensive losses in crops annually. While there are commercially available materials used to control many plant diseases.- further improvement in this art is needed if full food and fiber production is to be realized.
There are a large number of patent and literature references in the area of azole antifungal drugs and plant disease control agents. Host pertinent to the a-styryl carbinol compounds of this invention are the following references: B. Sugavanam in U.S. Patent 4.507.140 issued March 26. 1985 discloses fungicidal or plant growth regulating 0-styryl triazoles or imidazoles, amongst others of the formula: Z where R1 is CH«CH-X; -CEC-X or -CH2-CH2-X; X is substituted aryl. aralkyl. or heterocycle; 2 R is alkyl. cycloalkyl. or optionally substituted aryl; Z is OR3; 3 R is H. acetyl; Y is -N- or -CH-.
Australian patent'application 70557/81 discloses antimycotic agents of the formula: 2 234 84 1 ♦ * fv,'? f r«5* where amongst others R is alkyl. optionally substituted cycloalkyl or optionally substituted phenyl radical; X is N, or a CH group; Y is -OCH2-. -CH2CH2- or CH-CH; Z is halogen, alkyl, cycloalkyl. alkoxy. alkythio. etc.
Also known is a — : substituted 1-hydroxy-ethyl-triazole derivatives of the formula: OH \\—X—i—R l^\=J <U 20 a | 2 N. 4 jj" N— where amongst others 25 R is alkyl, cycloalkyl or phenyl optionally substituted; X is -0CH2-, -SCH2-. -(CH2)p or -CH=CH-: Z is halogen, alkyl. alkoxy. alkylthio. 3Q haloalkyl. haloalkoxy, or haloalkylthio; m and p are 0. 1 and 2.
The compounds are antimycotics for treating dermatophytomycoses and systemic mycoses caused, e.g., by Candida sp.. Aspergillus sp.. Trichophyton sp. 3 - ' 234 4 The above three references, which pertain to fi-styryl azoles, are believed to be the most relevant. The fl-styryl azole analog of one of the preferred compounds of the instant invention was prepared and found to be significantly less active.
European Patent Application 114,487 which published August 1, 1984 discloses azolylethanol derivatives of the formula: OH 1— H—CH^,—i—X—R2 W—N—CH_—C- » J i1 "N 1 2 Where amongst others R and R which may be the same or different are hydrogen, alkyl, cycloalkyl. 15 alkenyl, heterocyclyl aryl, or aralkyl optionally substituted; N is N or CH; and X is C«0. The compounds have fungicidal activity and plant growth regulating activity.
European Patent 117,578-A, published February 23, 20 1984 discloses heterocyclic-hydroxy-alkyl alkyl ketone(s) and analogues of the formula: R2—A—C—CH-0 i3 2 where A is CO amongst others; Q is imidazoyl or 1H- or 4H-1,2,4- triazol-l-yl; R1 is H, 1-5C alkyl, or 1-8C acyl; 4 234841 ; r> ; W 10 ; R2 and R3 are 1-5C alkyl. 3-6C cycloalkyl, 2-6C alkenyl, benzyl (optionally substituted by 1-3 halogen), pyridyl. furyl. thienyl. or phenyl optionally substituted by 1-3 halogen, 1-3 alkyl, or 1-3C alkoxy.
U.K. patent 2146987 —— —— : discloses 1-phenyl-l-azolyl-hydroxyethyl cycloalkane derivatives of the formula: ^ > oh ^L(CHR3)n^> B where R^ and R2 - H. halo, N02< lower alkyl, alkenyl, alkynyl. alkoxy or alkylthio (all optionally substituted by 1 or more halo), or optionally substituted phenyl or phenoxy; Rj « H or lower alkyl; R4 and R5 * H or halo; Y - CH or N; A » 2-7C alkylene; n » O or 1.
The compounds are useful as agricultural fungicides and antimycotics.
None of the cited references nor any known references suggest the intermediates, of this invention. 4& 234 84 1 The compounds of this invention are intermediates in the preparation of compounds of the formula: O S CRE1 2 3 ° i |\e or r3 l »-(ch ) :——c c—t/t (i) b i* V-1 or a pharraaceutically or agriculturally suitable salt iQ thereof wherein v*w"* * *■* E is a bond or an oxygen atom with the proviso that when E is oxygen; R. R1 are not halogen; A is perfluoroalkyl of 1-8 carbon atoms. 15 N(CH3)2< OH. naphthyl optionally substituted with a total of 1-3 substituents each of which is independently selected from halogen and -ty J. optionally substituted with 1 or 2 methyl groups, phenyl optionally substituted with a total of 1-3 substituents each of which is independently selected from: halogen, alkyl of 1-4 carbon atoms, haloalkyl of 1-4 carbon atoms, alkoxy of 1-4 carbon atoms, and with no more than one 25 group selected from: haloalkoxy of 1-4 carbon atoms.
S(0) R5. R,. 2-.3-.or 4-m 6 pyridyl. imidazol-l-yl. 1.2.4- triazol-l-yl. and -o optionally substituted with 1 or 2 methyl groups. or a heterocycle selected from imidazol-l-yl. 1.2.4-triazol-l-yl. 2-or 3-thienyl. and 2-.3-.or 4-pyridyl optionally substituted with one or two substituents each of which is independently selected from: halogen, alkyl of 1-4 carbon atoms, CF,, and S(0)m R5: 3 01 234 8 4 1 7 B is alkyl of 1-8 carbon atoms, naphthyl. biphenyl. ch2 6 A perfluoroalkyl of 1-8 carbon atoms, phenyl optionally substituted with 1-3 substituents each of which is independently selected from: halogen, alkyl of 1-4 carbon atoms, haloalkyl of 1-4 carbon atoms, alkoxy of 1-4 carbon atoms, and with no more than one group O 10 selected from haloalkoxy of 1-4 carbon atoms, or S(O) R5. m benzyl optionally substituted on the phenyl ring with halogen or alkyl of 1-4 carbon atoms, or optionally a-substituted with 1 or 2 methyl groups, or a heterocycle selected from 2-or 3-thienyl, and 2-,3-.or 4-pyridyl optionally substituted with one or two substituents each of which is independently selected from: halogen, alkyl of 1-4 carbon atoms, CF_, or S(O) R5; 3 m O O Q is H. halogen. S(0) R11. SCNHR12. CHO. C-CH,.
TO 3 13 12 COjR . SCN. SSR . or SH or its corresponding disulfide, provided however that when Q is _ _ 14 other than H. then n is O, R. R . and R 3 are independently H or CH3> R is H. and A and B are each phenyl optionally substituted with from 1-3 substituents each of which is independently halogen. CH3» 35 CF3. OCH3. or S(0)mR5; ■ — —- 234841 c n is 0-4 with the proviso that when A is -•TV \ t N(CHj)2. or OH. then n is other than O; iu each occurrence is 0. 1 or 2; X is C. NR10. or O; R and R1 independently are H. alkyl of 1-4 carbon atoms, halogen, or phenyl, or taken together form cycloalkyl of 3-7 carbon atoms; 2 R is H, allyl, propargyl, alkyl of 1-4 carbon 3 t OIQS f o o o « 7 ii A Q ii *7 -CR . -C-NR°R . -COR . or haloalkyl of 1-4 carbon atoms; 3 4 .
R and R independently are H. F. or alkyl of 1-4 carbon atoms; R5 is alkyl of 1-4 carbon atoms; 6 R is phenyl optionally substituted with a total of 1-3 substituents each of which is independently selected from halogen and CF3; 7 R is alkyl of 1-4 carbon atoms, phenyl, or benzyl; 8 9 R and R independently are H. alkyl of 1-4 carbon atoms, phenyl or benzyl; RL0 is H. alkyl of 1-4 carbon atoms, or acetyl: " T-.vC-.-M"^ •/1 234 84 1 R li is alkyl of 1-4 carbon atoms, haloalkyl of 1-4 carbon atoms. CH2CN. CH2SCN, CH(CH3)CN. CH2C02CH3. or CH2COzCH2CH3; .12 is alkyl of 1-4 carbon atoms, allyl. phenyl optionally substituted with 1-2 substituents each of which is independently halogen. CH3> or OCH3. or benzyl optionally substituted with 1-2 substituents each of which is independently halogen. CH3» or OCH3; and .13 is H. or alkyl of 1-4 carbon atoms. 7--W S- 234841 o o This invention provides compounds of the formulae (II) and (Ila) shown below: 1 4 (ii) R and R are not F or both alkyl; CRR^Q CRR OH ) 4_C—JCR3R4 A (CH_ ) J: C CR3R4 2 n , 2 n , , 8 B X (II) 13 4 in which, in formula (II), A, B, R, R , R , R and n are as defined above with the provisos that 1 2 (i) A and B are not both phenyl when R, R and R are H and n=0; and (ii) R3 13 4 and in formula (Ila), A, B, R, R , R , R and n are as 3 defined above and X is Br, Cl, or I with the proviso that R 4 and R are not F or both alkyl.
Preferred compounds of the formula (I) are the ec-styryl compounds (E is a bond) where: 1) n m o, or 1; and/or 3 4 2) R and R independently are H. CH3# or F.
More preferred compounds of the formula (i) are compounds where: 1) A, and B independently are phenyl optionally substituted with from 1-3 substituents each of which is halogen, alkyl of 1-4 carbon atoms, haloalkyl of 1-4 carbon atoms, alkoxy of 1-4 carbon atoms, or S(O) R5; and/or m 2) n « 0; and/or 3) R and R1 independently are H. CH3 or halogen; and/or 2 4) R « H. alkyl of 1-4 carbon atoms, allyl. or propargyl; and/or ) Q is H. I. SH. 234 84 1 11 Most preferred compounds ofvformula (I) are compounds where: 1) A and B independently are phenyl optionally substituted with from 1-3 halogen atoms. CH3» OCH3. _ CF . or SCH_; and/or: b 3 3 2) R. R1. R2. R3. R4 and Q are all H.
Specifically preferred because of their biological activity are the following compounds or salts thereof: (a) 2-(4-Fluorophenyl)-3-phenyl-l-(lH-1.2.4-tri- azol-l-yl)-3-buten-2-ol; and the (S) enantiomer thereof. (b) 2.3-Bis(4-fluorophenyl)-l-(lH-1.2,4-triazol-l-yl)-3-buten-2-ol; and the (S) enantiomer thereof. (c) 2-(2.4-Dichlorophenyl)-3-(4-chlorophenyl)- 1-(1H-1,2.4-triazol-l-yl)-3-buten-2-ol; and the (S) enantiomer thereof. (d) 2-(4-Chlorophenyl)-3-(2-chlorophenyl)-3-buten-2-ol; and the (S) enantiomer thereof. (e) 2-(2,4-Dichlorophenyl)-3-(3-fluorophenyl) -1- (lH-1.2.4-triazol-l-yl)-3-buten-2-ol; and the (S) enantiomer thereof. (f) 2-(2-Chlorophenyl)-3-(2-chlorophenyl)-l-(1H-1,2.4—triazol-l-yl)-3-buten-2-ol; and the (S) enantiomer thereof. (g) 2-(2.4-Dichlorophenyl)-3-(3-chlorophenyl)-1-(1H-1.2,4—tr iazol-l-yl)-3-buten-2-ol; and the (S) enantiomer thereof. (h) 2-(4-Fluorophenyl)-3-(4-tr ifluororaethylphen- yl)-l-(lH-l.2.4-triazol-l-yl)-3-buten-2-ol; and the (S) enantiomer thereof. (i) 2-(2.4-Dichlorophenyl)-3-phenyl-1-(1H-1.2.4-triazol-l-yl)-3-buten-2-ol; and the (S) enantiomer thereof. 11 o 23 4 8 4 1 12 (j) 2-(3.4-Dichlorophenyl)-3-(4-fluorophenyl)-l-(lH-1.2.4-triazol-l-yl)-3-buten-2-ol; and the (S) enantiomer thereof. (k) 2-(4-Chlorophenyl)-3-(3-chlorophenyl)-l-5 (1H-1.2.4-triazol-l-yl)-3-buten-2-ol; and the (S) enantiomer thereof. (1) 2-(4-Fluorophenyl)-3-(2.4-difluorophenyl)-l-(lH-1.2#4-triazol-l-yl)-3-buten-2-ol; and the (S) enantiomer thereof. (m) 2-(2,4-Difluorophenyl)-3-(2-chlorophenyl)- (1H-1,2,4-triazol-l-yl)-3-buten-2-ol; and the (S) enantiomer thereof. (n) 2-(2,4-Difluorophenyl)-3-phenyl-l-(1H-1.2.4-triazol-l-yl)-3-buten-2-ol; and the (S) enantiomer thereof. (o) 2-(2.4-Difluorophenyl)-3-(4-fluorophenyl)-l-(lH-1.2.4-triazol-l-yl)-3-buten-2-ol; and the (S) enantiomer thereof. (p) 2-(2-Fluorophenyl)-3-(4-fluorophenyl)-l-(lH-1.2.4-triazol-l-yl)-3-buten-2-ol; and the (S) enantiomer thereof. (q) 2-(2-Fluorophenyl)-3-(4-chlorophenyl)-l-(lH-1.2,4-triazol-l-yl)-3-buten-2-ol; and the (S) enantiomer thereof. (r) 2-(2.4-Difluorophenyl)-3-(4-chlorophenyl)-l-(lH-1.2,4-triazol-l-yl)-3-buten-2-ol; and the (S) enantiomer thereof. (s) 2-(2-Chlorophenyl)-3-(4-fluorophenyl)-l-(lH-1.2.4-triazol-l-yl)-3-buten-2-ol; and the (S) enantiomer thereof. (t) 2-(4-Chlorophenyl)-3-phenyl-l-(1H-1.2,4-triazol-l-yl)-3-buten-2-ol; and the (S) enantiomer thereof. 12 234 84 1 13 All of the compounds of formula (I) —• »— !—are active in either pharmaceutical or agricultural fungicidal assays. Thus, it should be recognized that there are compounds which are not 5 always active in both assays as is shown with some compounds in the Examples. Of the above listed specifically preferred compounds, compounds (a)-(n) or their salts are preferred for pharmaceutical uses and compounds (n)-(t) or their salts are preferred for agricultural uses. 13 i 23 4 8 4 1s v o 14 Synthesis The compounds of Formula (I) can be prepared using the reactions and techniques described 5 in this section. The reactions are usually performed in a solvent appropriate to the reagents and materials employed, and suitable for the transformation being effected. In some cases functional groups on the starting materials may need O 10 to be protected by standard protecting groups reported in the chemical literature which are well known to one skilled in the art.
In some cases, substituents on the starting materials may be incompatible with some of the 15 reaction conditions required in some of the methods described. Such restrictions to the substituents which are compatible with the reaction conditions will be readily apparent to one skiriled in the art and alternative methods described must then be used.
The compounds of formula I — . can contain at least one chiral center and as such can exist as two individual isomers or as a racemic mixture of both. The (S) isomer, as well as to racemic mixtures containing 25 both isomers,, are intended. ' —_l—: : : The (S)-isoraer of compounds of Formula (I) is intended to mean compounds of the configuration depicted: A-(CH,) CRR1 , Q j> ?E R ^ a-..-4—r,c-v b w (la) When a single chiral center is present the resolution can be performed by reacting the compound 14 -Ar> 234 84 1 n n S~> with a chiral strong acid (e.g. substituted camphor-sulfonic acids) in a suitable solvent (e.g. aceto-nitrile) or mixture of solvents (e.g. 3/1 ether-acetone). This reaction i6 carried out at a temperature between 25°C to 100°C. preferably at the reflux temperature of the solvent(s) employed. The reaction produces two diastereomeric adducts that can be separated by fractional crystallization. The adduct can then be cleaved in basic medium (e.g. sat. NaHCOj, sat. Na2C03) to give the resolved product.
The compounds of Formula I. where E is a bond. 2 3 4 R and Q are H and R . R are not F and not both alkyl, can be prepared by contacting an oxirane of Formula (II) or a halohydrin of Formula (Ha), or a mixture of (II) or (Ila) with triazole or its alkali metal salt (preferably the Na+ or K+ salt) in a suitable solvent (Scheme I).
• Scheme 1 I CRR n ,IA, B (ID and/or + f N-M N^/ solvent CRR OH 1 3 4 -C-CR R ■ i B X (Ila) A<CH2>n CRR1 OH R3 R4 Hr, B (I) X * I. Br, Cl: M = H. alkali metal i O 234 84 1 16 When triazole is used, an acid acceptor, such as potassium carbonate, sodium methoxide or sodium hydride, is added to the reaction mixture. Suitable inert solvents include polar, aprotic solvents 6uch as 5 dimethylformaraide (DMF). dimethylsulfoxide (DMSO) and ethereal solvents such as tetrahydrofuran (THF). Non-polar solvents, such as toluene, may be used if a phase transfer catalyst, such as tetrabutylararaonium bromide, is added. The reaction is carried out at a 10 temperature in the range of 10° to 150°C. preferably from 50° to 120°C. for a period of 0.25 to 24 hours. It is recognized that varying amounts of the 4H-1.2.4-triazol-4-yl isomers of Formula (I) may be formed in the above reaction. The isomers can be 15 separated, if desired, using standard separation techniques, e.g.. chromatography.
The oxiranes of Formula (II) can be prepared using one or both of the following methods; (Scheme 2). In the first, vinyl organometallic reagents. 20 e.g.. vinyl Grignard reagents, of Formula (III) are allowed to react with haloketones of Formula (IV) in the presence of ethereal solvents, such as THF or diethyl ether, at a temperature ranging from -90° to 60°C. preferably -10° to 50°C. for 0.5 to 24 hours. 25 Depending on the reaction conditions and the value of X in the haloketone starting material (IV). the product may be an oxirane (II). a halohydrin (Ila) or a mixture of (II) and (Ila). If desired, the halohydrin6 (Ila) may be converted to oxiranes (II) by 30 treatment with base, e.g., potassium hydride (KH), in a solvent such as THF. 16 b, 234 84 1 o n 17 Scheme 2 CRR O A(CH_) C-M + B-C-C-X 2'n " " w/\~" THF F*\ 3,.
* A(CH_ ) C-C-——CR R b ll I (Ila) R3 R4 (III) (IV) M=MgX, Li X-Cl. Br. I X-Cl. Br. I ? A A-(CH2)n-C-C—^CR3R4 + Ph3P-CRR1 B * (II) A KH B (V) In the second method, keto-oxiranes of formula (V) are olefinated with, for example. Wittig reagents, which provide epoxy-olefins of Formula (II). 20 Unsaturated ketones of Formula (VII) can be converted to expoxy-olefins (II) by treatment with dimethylsulfonium methylide. The enones (VII) can be prepared by treatment of ketones of Formula (VI) with carbonyl compounds and appropriate catalysts (Scheme 25 3).
Scheme 3 A(CH_) CH-CB 30 2 n 2 RR'C=»0 CRR A(cH2)nC-CB L + - (CH3)2SCH2 -> (II) (VI) (VII) 17 234 8 18 Unsaturated ketones of Formula (VIII) can be converted to epoxyketones (V) using basic hydrogen peroxide. Olefination of (V), as described above, provides epoxyolefins (II) (Scheme 4).
Scheme 4 2 2 O ACCH2>„C-C-B NaQH > AtCHjJ^-B > (II) CR3E4 *0 3 4 CR R (VIII) (V) The vinyl organometallics of Formula (III) are prepared using standard procedures from the corresponding chlorides, bromides or iodides. The haloolefins. the haloketones of Formula (IV). the keto-oxiranes of Formula (V) and the ketones of Formula (VI) are known, or can be prepared using methods known to one skilled in the art.
Compounds of Formula (I) can also be prepared by olefination of ketones (IX) with, for example, Wittig reagents (Scheme 5). Ketones of Formula (IX) where R2. R3 and R4 ■ H are known (EP 117578A).
Scheme 5 . . . CRR « . .
O OR2 R3 R4 , II OR R R4 R R~ . OR R R" A(CH„)C-C Ph3P-CRR A(CH0) C-C n ' V^N > A \^N b b (IX) (I) 18 234 8 4 1 19 Compounds of general Formula (I) where R3 and/or 4 R ¥ H can be made as shown in Scheme 6 by reacting ketones of general Formula (X) with the appropriate organoraetallic reagent (e.g. Grignard reagent, organolithiura reagent). The ketones (X) are prepared by conventional methods from the corresponding a-haloketones (IV) (see e.g. EP 0044605. UK 2099818A. UK 146224, EP 1337718. and EP 0153803).
Scheme 6 a, e3 r4 r3 r4 (iv) (x) X-Br, Cl. I b) (X) + A-(CH2)n/EfM (I) (III) M»MgX. Li X-Cl, Br, I Compounds of Formula (I) where A=(heterocycle)-phenyl can be prepared from appropriately substituted precursors using the methods described above, or by 30 using substitution reactions on (I) wherein A is halophenyl. For example, compounds of Formula (I) where A is (pyridyl)phenyl can be prepared by treatment of (I), wherein A is bromophenyl or iodophenyl. with the appropriate pyridylstannanes in 19 i i n ° 234 84 1 the presence of palladium catalysts (see Tetrahedron Letters. 21_. 4407. 1986). Copper assisted displacement of halogen (Tetrahedron. 4(). 1433. 1984) with heterocyclic nucleophiles provides compounds of 5 Formula (I) where A is for example 1-iraidazolylphenyl.
In some cases, it may be desirable to begin with compounds of Formula I. wherein A is aminophenyl, and construct the heterocyclic ring using X(CH2CH2C1)2 (see ES 8603-473-A).
The compounds of Formula (I) where Q*H can be prepared as shown in Scheme 7. Metalation of (I). Q»H with strong base provides the 5-metalated triazoles (la) (See Heterocycles. 23. 1645-49. 1985). When R2 is H. 2 equivalents of base are required. Typical 15 conditions involve treatment of a solution of (I) in THF at -70° with n-butyllithium for 15-30 minutes. Where the metalated triazole (la) is less soluble than (I), the addition of co-solvents, such as dimethylpropyleneurea (DHPV) may be beneficial.
Scheme 7 I?®1*1 2 d4 1 CRR1 OR2 R4 fl OR R strong c—c—^7 )» AC- B H (I) 1 2 4 9 CRR1 ORZ R ^ electrophiles ^ A_n 1 t \o > AC C C (I) <I»> > . 1 \ B H • ••.. ... .. • f 234841 © 21 The treatment of (la) with electrophiles gives a wide variety of (I) where Q ¥ H. Electrophiles of relevance include halogenating agents, sulfur, disulfides, carbon dioxide, diraethyl-5 amides and sulfur dioxide followed by alkyl halides. Subsequent functionalization. using methods known to one skilled in the art. provide other compounds of Formula (I) wherein Q ¥ H. For example, the treatment of (I), where Q is SH with isocyanates or 1Q phthalimidosulfides provides thiocarbamates (I: ° \ 12\ 12 0 - SCNHR yor disulfides (I; Q - SSR ), respectively.
The compounds of general Formula (I) where E i6 oxygen can be prepared by oxidation of compounds of IS general Formula (I) where E is a bond provided that R, R1 ¥ halogen using methods described in the literature (Scheme 8): Scheme 8 CRR —> A<CtVn- Suitable reagents which can effect this oxidation. depending on the nature of the substituents. include peracids such as m-chloroperbenzoic acid; hydroperoxides such as tert-butyl hydroperoxide in the presence of an appropriate catalyst such as vanadium acetonylacetonate; or hydrogen peroxide. Alterna-35 tively. the transformation can be effected by first 21 23 4 8 4 1 22 forming the halohydrin with a hypohalous acid such as hypobroraous acid and then reacting the intermediate halohydrin with a proton acceptor such as potassium tert-butoxide.
It will be noted by those skilled in the art that, depending on the nature of the compound to be oxidized, a mixture of diastereomers can be obtained. This can be controlled through selection of appropriate oxidation methods or. alternatively, the resulting mixture of diastereomers can be separated in a conventional manner (e.g. chromatography, fractional crystallization). 2 Compounds of Formula (I) where R is H can be alkylated, acylated and carbamoylated. using standard 15 procedures, to prepare functional derivatives of the alcohol moiety.
The compounds of this invention and their preparation can be understood further by the following examples, but should not constitute a limitation 2Q thereof. In these examples, unless otherwise indicated, all temperatures are in degrees centigrade and parts and percentages are by weight.
Nuclear magnetic resonance (nmr) spectra were obtained in CDCl^ solution, unless otherwise noted. Abbreviations for nmr spectra are s-singlet. d=doublet. t»triplet. q«quartet. m=multiplet; peak positions are reported as parts per million downfield from tetramethylsilane. 22 234 84 1 23 Example 1 PART A: 2-(4-Fluorophenyl)-2-[1-(4-fluorophenyl)- ethenyl] oxirane PROCESS 1: Grignard Addition to an a-Haloketone To a 25° solution of Grignard reagent prepared from 6.0 g (0.030 mol) of l-brorao-4'-fluorostyrene and 0.85 g (0.035 raol) of magnesium turnings in 60 mL of THF was added a solution of 5.2 g (0.030 mol) of 2-chloro-4'-fluoroacetophenone in 10 mL of THF. The solution was 6tirred for 2 hours at 25°. Saturated aqueous NH^Cl (10 mL) was added, the aqueous layer was extracted with 1:1 EtzO/hexane and the combined organic layers were washed with brine, dried over 15 MgS04 and evaporated to give 10.2 g of an amber oil. Analysis by NMR (CDC13) indicated that the desired oxirane was the major product: 6 3.1. 3.3 (two d. epoxide protons; 5.5, 5.8 (two s. vinyl protons). The material was of sufficient purity to be used in the 2Q next step.
PROCESS 2: Olefination of 2-(4-Fluorophenyl)-2-(4-fluorobenzoyl)oxirane To a suspension of 4.3 g (0.012 mol) of methyltriphenylphosphonium bromide in 15 mL of THF cooled to -70° was added 8.4 mL (0.013 mol) of 1.55 M n-butyllithium over 3 tain., keeping the temperature at less than -55°. The resulting yellow suspension was allowed to warm to 0° over 10 rain, and was then treated with 2.6 g (0.010 mol) of 2-(4-fluorophenyl)-2-(4-fluorobenzoyl)oxirane in 5 mL of THF. The light-brown suspension was stirred for 6 hours at 25°. Standard workup gave 3.4 g of crude product which was flash chromatographed (Et20) to give 1.7 g 23 234 84 1 24 of the desired product, which was of sufficient purity to be used in the next step. NMR (CDC13) 6 3.1 (d): 3.3 (d); 5.5 (s): 5.8 (s).
PART B: 2.3-Bis (4-Fluorophenyl)-l-(lH-1.2.4-triazol-l-yl )-3-buten-2-ol A mixture of 10.2 g (0.030 raol) of crude 2-(4-fluorophenyl)-2-[l-(4-fluorophenyl)ethenyl]oxirane and 7.0 g (0.065 mol) of potassium triazole in 60 mL of DMF was heated at 60° overnight, then cooled and poured into 100 mL of 1:1 Et20/hexanes. After washing the organic layer three times with H20 and once with brine, a precipitate formed in the organic layer. Filtering gave 4.8 g of a brown solid which was recrystallized from 500 mL of cyclohexane to yield 2.5 g of a light-tan powder, mp 136-137°: NMR (CDC13) 6 1.7 (br s. OH); 4.7 (q. 2H); 5.3 (s. 1H); 5.5 (s. 1H); 6.8-7.1 (m. 6H); 7.4 (m. 2H); 7.8 (s. 1H); 7.9 (s. 2£) 1H); IR (nujol) 3120 (br). 1900. 1600. 1505. 1220. 1139. 835 cm"1.
% The compounds shown in Table 1 were prepared or can be prepared by the method described hereinabove.
In the tables. Ph means phenyl and substituted aryl groups are abbreviated, e.g.. 4-F-Ph is 4-fluorophenyl. 2.4-Cl2~Ph is 2.4-dichlorophenyl and 2-thienyl is thiophen-2-yl. 24 © 23484 1 Table 1 CRR A(CH,y 2 n 2 08 C~\£ Ex. No. _ _1 _2 _3 _4 n R R R R R M.P. *C 1 4-F-Ph 4-F-Ph 0 H H H H H 136-137 (HCl salt 182-184) 2 4-F-Ph 2,4-Cl2-Ph 0 H H H H H 139-143 3 4-F-Ph 4-Cl-Ph 0 H H H H H (oil)a 4 4-F-Ph 2,4-F2-Ph 0 H H H H H 102-103.5 4-F-Ph 4-CF3-Ph 0 H H H H H 6 4-F-Ph n_C4H9 0 H H H H H 72-73 7 4-F-Ph ~~C4F9 0 H H H H H 8 2-F-Ph Ph 0 H H H H H 9 2-F-Ph 2-F-Ph 0 H H H H H 89-93 2-F-Ph 4-F-Ph 0 H H H H H (oil)b 11 2-F-Ph 2,4-F2-Ph 0 H H H H H 121-122 12 2-F-Ph 2-Cl-Ph 0 H H H H H 13 2-F-Ph 4-Cl-Ph 0 H H H H H 116-117 14 2-F-Ph 2,4-Cl2-Ph 0 H H H H H 115-116 3-F-Ph 4-F-Ph 0 H H H H K 106-109 16 3-F-Ph 2,4-Cl2-Ph 0 H H H H H 145-14 7 17 3-F-Ph 4-Cl-Ph 0 H H H H H 101-102 18 3-F-Ph 2,4-F2-Ph 0 H H H H H 19 3-F-Ph 4-CF3-Ph 0 H H H H H 3-F-Ph -~C4H9 0 H H H H H f) o 26 Table 1 (Continued) EX- 12 3 4 No. A B SELLLL H.P.'C 21 3-F-Ph n-CAF. 0 H H H H H ~ 4 9 22 3-F-Ph Ph 0 H H H H H 23 3-F-Ph 2-F-Ph O H H H H H 24 3-F-Ph 2-Cl-Ph 0 H H H H H ("""l 25 4-Cl-Ph 4-F-Ph 0 H H H H H 110-115 W 10 26 4-Cl-Ph 2,4-Cl -Ph 0 H H H H H 89-91 (HCl salt 184-190) 27 4-Cl-Ph 4-Cl-Ph 0 H H H H H 132-135 28 4-Cl-Ph 2,4-F2-Ph 0 H H H H H 124-125.5 29 4-Cl-Ph 4-CF3-Ph O H H H H H 4-Cl-Ph n-C.H 0 H H H H H — 4 9 31 4-Cl-Ph n-C.F O H H H H H — 4 9 32 2-Cl-Ph 4-F-Ph 0 H H H H H (oil)C 20 33 2-Cl-Ph 2,4-Cl2-Ph 0 H H H H H 150-152 34 2-Cl-Ph 4-Cl-Ph 0 H H H H H 153-154 (HCl salt 175-180) O 35 2-Cl-Ph 2,4-F -Ph 0 H H H H H 128-129 (HCl salt 156-161) 36 2-Cl-Ph 4-CF3-Ph 0 H H H H H 37 2-Cl-Ph n-C.H_ 0 H H H H H jms. - 4 9 38 2-Cl-Ph n-C.F 0 H H H H H 39 3-Cl-Ph 4-F-Ph 0 H H H H H 95-96.5 40 3-Cl-Ph 2,4-Cl2-Ph 0 H H H H H 144-146 41 3-Cl-Ph 4-Cl-Ph 0 H H H H H 112-115 26 234 84 1 W? n G 27 Table 1 (Continued) Ex. Mo.
A B n R R [ R 2 d3 „4 R R M.P.'C 42 3-Cl-Ph 2,4-F2-Ph 0 H H H H H 115-116 43 3-Cl-Ph 4-CF3-Ph 0 H H H H H 44 3-Cl-Ph a~C4H9 0 H H H H H 45 3-Cl-Ph n-c4F9 0 H H H H H 46 3-Cl-Ph Ph 0 H H H H H 47 3-Cl-Ph 2-F-Ph 0 H H H H H 91-93 48 3-Cl-Ph 2-Cl-Ph 0 H H H H H 49 Ph 4-F-Ph 0 H H H H H 125-126 50 Ph 2t4-Cl2-Ph 0 H H H H H 117-120 51 Ph 4-Cl-Ph 0 H H H H H 111 52 Ph 2,4-F2-Ph 0 H H H H H 119.5-122 (HCl salt 152-154) 53 Ph 4-CF3-Ph 0 H H H H H 54 Ph —"C4H9 0 H H H H H 55 Ph *-C4F9 0 H H H H H 56 2-CF3-Ph Ph 0 H H H H H 57 2-CF3-Ph 2-F-Ph 0 H H H H H 58 2-CF3-Ph 2-Cl-Ph 0 H H H H H 59 3-CF3-Ph Ph 0 H H H H H 60 3-CF3-Ph 2-F-Ph 0 H H H H H 61 3-CF3-Ph 2-Cl-Ph 0 H H H H H 62 4-CF3-Ph Ph 0 H H H H H 63 4-CF3-Ph 2-F-Ph 0 H H H H H 64 4-CF3-Ph 2-Cl-Ph 0 H H H H H 27 i 234 84 1 28 Table 1 (Continued) O o Ex. No.
B 65 4 66 4 67 4 68 4 -CF3-Ph -CF3-Ph -CF3-Ph -CF3-Ph 4-F-Ph n R R_ 0 H H 2,4-Cl2-Ph 0 H H 2 3 4 R R R M.P.'C H H H 152-154 H H H 4-Cl-Ph 0 H H H H H 144-145 2,4-F2-Ph 0 H H H H H 69 4-CF3~Ph 4-CF3-Ph 0 H H H H H 70 4-CF3-Ph n~C4H9 0 H H H H H 71 4-CF3-Ph -"C4F9 0 H H H H H 72 2-Br-Ph Ph 0 H H H H H 73 2-Br-Ph 2-F-Ph 0 H H H H H 74 2-Br-Ph 4-F-Ph 0 H H H H H 75 2-Br-Ph 2,4-F2-Ph O H H H H H 76 2-Br-Ph 2-Cl-Ph O H H H H H 77 2-Br-Ph 4-Cl-Ph O H H H H H 78 2-Br-Ph 2,4-Cl2-Ph O H K H H K 79 3-Br-Ph Ph O H H H K H 80 3-Br-Ph 2-F-Ph O H H H K H 81 3-Br-Ph 2-Cl-Ph O H H H H H 82 4-Br-Ph Ph O H H H H H 83 4-Br-Ph 2-F-Ph O H H H H H 84 4-Br-Ph 2-Cl-Ph O H H H H H 85 4-Br-Ph 4-F-Ph 0 H H H H H 86 4-Br-Ph 2,4-Cl2-Ph 0 H H H H H 87 4-Br-Ph 4-Cl-Ph 0 H H H H H 88 4-Br-Ph 2,4-F2~Ph 0 H H K H H 89 4-Br-Ph 4-CFj-Ph 0 H H H H H 90 4-Br-Ph S-C4H9 0 H H H H H (oil) 28 234 84 1 *®£S 29 Table 1 (Continued) G Ex. No. o 91 4-Br-Ph 92 2,4-F2-Ph 93 2,4-F2-Ph 94 2,4-F2-Ph 95 2,4-F -Ph 2 96 2,4-F2-Ph 97 2,4-Fj—Ph 98 2,4-F2-Ph 99 2,4-Cl-Ph 2 100 2,4-Cl2-Ph 101 2,4-Cl2-Ph 102 2,4-Cl2-Ph 103 2,4-Cl2-Ph 104 2,4-Cl2-Ph 105 "2,4-Cl2-Ph 106 2,4-Cl2-Ph 107 2,4-Cl2-Ph 108 2,4-Cl2-Ph 109 3,4-Cl2-Ph 110 3,4-Cl2-Ph 111 3,4-Cl2-Ph 112 4-t-Bu-Ph 113 4-t-Bu-Ph n-c4F9 Ph 2-F-Ph 4-F-Ph 2,4-F -Ph 2 2-Cl-Ph 4-Cl-Ph 2,4-Cl2-Ph 4-F-Ph 2,4-Cl2-Ph 4-Cl-Ph 2,4-F2-Ph 4-CF3-Ph n-c4H9 a"C4F9 Ph 2-F-Ph 2-Cl-Ph Ph 2-F-Ph 2-Cl-Ph Ph 2-F-Ph n R R1 R2 R3 R4 M.P.'C 0 H H H H H 0 H H H H H O H H H H H 106-108 0 H H H H H 100-103 0 H H H H H 116-120 0 H H H H H 0 H H H H H 0 H H H H H 0 H H H H H (oil)® 0 H H H H H 75-78 0 H H H H H 60-62 0 H H H H H 106-109 0 H H H H H O H H H H H O H H H H H 0 H H H H H 0 H H H H H 68-73 0 H H H H H 0 H H H H H 0 H H H H H 0 H H H H H 0 H H H H H 0 H H H H H 29 ? 234 84 1 n Table 1 (Continued) E*' 12 3 4 No. A B n R R_ R_ R_ R_ M.P.'C 114 4-t-Bu-Ph 4-F-Ph 0 H H H H H 110-113 115 4-t-Bu-Ph 2,4-F^-Ph 0 H H H H H 116 4-t-Bu-Ph 2-Cl-Ph 0 H H H H H 117 4-t-Bu-Ph 4-Cl-Ph 0 H H H H H (oil)f 10 118 4-t-Bu-Ph 2,4-Cl^—Ph 0 H H H H H 119 2-CH3S-Ph Ph 0 H H H H H 120 2-CH3S-Ph 2-F-Ph 0 H H H H H 121 2-CH3S-Ph 4-F-Ph 0 H H H H H 15 122 2-CH3S-Ph 2,4-F2-Ph 0 H H H H H 123 2-CH3S-Ph 2-Cl-Fh 0 H H H H H 124 2-CH^S-Ph 4-Cl-Ph 0 H H H H H 125 2-CHjS-Ph 2,4-Cl2-Ph 0 H H H H H 126 2-CH3S(0)-Ph Ph 0 H H H H H 127 2-CH3S(0)-Ph 2-F-Ph 0 H H H H H 128 2-CH3S(0)-Ph 4-F-Ph 0 H H H H H 129 2-CH3S(0)-Ph 2,4-F2-Ph 0 H H H H H 130 2-CH3S(0)-Ph 2-Cl-Ph 0 H H H H H 131 2-CH3S(0)-Ph 4-Cl-Ph 0 H H H H H 132 2-CH3S(0)-Ph 2,4-Cl2-Ph 0 H H H H H 3Q 133 2-CH3S(0)2-Ph Ph 0 H H H H H 134 2-CH3S(0)2-Ph 2-F-Ph 0 H H H H H 135 2-CH3S(0)2-Ph 4-F-Ph 0 H H H H H 136 2-CH3S(0)2-Ph 2,4-F2-Ph 0 H H H H H 'W>HS?SSnS!»^v > J, '''" - ' '•'' - ''" 234 84 1 31 Table 1 (Continued) Ex.
No. A B r v^y 137 2-CH3S(0)2-Ph 2-Cl-Ph 138 2-CH3S(0)2-Ph 4-Cl-Ph 139 2-CH3S(0)2-Ph 2,4-Cl2-Ph 140 3-CH3S-Ph Ph 141 3-CH3S-Ph 2-F-Ph 142 3-CH3S-Ph 4-F-Ph 143 3-CH3S-Ph 2,4-F2-Ph 144 3-CH3S-Ph 2-Cl-Ph 145 3-CH3S-Ph 4-Cl-Ph 146 3—CHjS—Ph 2,4-Cl2-Ph 147 3-CH3S(0)-Ph Ph 148 3-CH3S(0)-Ph 2-F-Ph 149 3-CH3S(0)-Ph 4-F-Ph 150 3-CH3S(0)-Ph 2,4-F2-Ph 151 3-CH3S(0)-Ph 2-Cl-Ph 152 3-CH3S(0)-Ph 4-Cl-Ph 153 3-CH3S(0)-Ph 2,4-Cl2-Ph 154 3-CH3S(0)2-Ph Ph 155 3-CH3S(0)2-Ph 2-F-Ph 156 3-CH3S(0)2-Ph 4-F-Ph 157 3-CH3S(0)2-Ph 2,4-F2-Ph 158 3-CH3S(0)2-Ph 2-Cl-Ph 159 3-CH3S(0)2-Ph 4-Cl-Ph 160 3-CH3S(0)2-Ph 2,4-Cl2-Ph n R R1 R2 R3 R4 M.P.'C 0 H H H H H 0 H H H H H 0 H H H H H 0 H H H H H 0 H H H H H 0 H H H H H 0 H H H H H 0 H H H H H 0 H H H H H 0 K H H H H 0 H H H H H 0 H H H H H 0 H H H H H 0 H H H H H 0 H H H H H 0 H H H H H 0 H H H H H 0 H H H H H 0 H H H H H 0 K H H H H 0 H H H H H 0 H H H H H 0 H H H H H 0 H H H H H 31 jmmKmismmKsmmim-j/Zisxzsi* srasMtwv — i I r 234 8 32 Table 1 (Continued) Ex • Wo. A B n R r!r! Hi M.P.'C 161 4-CH3S-Ph Ph O H H H H H 162 4-CH3S-Ph 2-F-Ph 0 H H H H H 163 4-CH^S-Ph 4-F-Ph O H H H H H 140-142 164 4-CH.S-Ph 2,4-F -Ph 0 H H H H H 81-83 \ 10 165 4-CH3S-Ph 2-Cl-Ph 0 H H H H H 166 4-CH3S-Ph 4-Cl-Ph 0 H H H H H 167 4-CH3S-Ph 2,4-Cl2-Ph 0 H H H H H 168 4-CH3S(0)-Ph Ph 0 H H H H H 169 4-CH3S(0)-Ph 2-F-Ph O H H H H H . 170 4-CH3S(0)-Ph 4-F-Ph 0 H H H H H 81-84 171 4-CH3S(0)-Ph 2,4-F2-Ph 0 H H H H H 131-134 172 4_CH3St0)-Ph 2-Cl-Ph 0 H H H H H i : 173 4-CH3S(0)-Ph 4-Cl-Ph 0 H H H H H 174 4-CH3S(0)-Ph 2,4-Cl2-Ph 0 H H H H H 175 4-CH3S(0)2-Ph Ph 0 H H H H H 25 176 4-CH3S(0)2-Ph 2-F-Ph 0 H H H H H 177 4-CH3S(0)2-Ph 4-F-Ph 0 H H H H H 135 178 4-CH3S(0)2-Ph 2,4-F2-Ph 0 H H H H H 179 4-CH3S(0)2-Ph 2-Cl-Ph 0 H H H H H 180 4-CH3S(0)2-Ph 4-Cl-Ph 0 H H H H H 181 4-CH3S(0)2-Ph 2,4-Cl2-Ph 0 H H H H H 32 ~ 23 4 ^4 1 o <& 10 siSs 33 Table 1 (Continued) EX' 12 3 4 Ho. A B n R R R R R M.P.T 182 3-n-BuS(0) -Ph 4-F-Ph 0 H H H H H 183 3-n-BuS(0) -Ph 2,4-F2-Ph 0 H H K H H 184 3-n-BuS(0) -Ph 4-Cl-Ph 0 H H H H H 185 3-n-BuS(0) -Ph 2-4-Cl2-Ph 0 H H H H H 186 2-CF30-Ph Ph 0 H H H H H 187 2-CF^O-Ph 2-F-Ph 0 H H H H H 188 2-CF30-Ph 4-F-Ph 0 H H H H H 189 2-CF30-Ph 2,4-F2-Ph 0 K H K H H 190 2-CF30-Ph 2-Cl-Ph 0 H H H H H 191 2-CF30-Ph 4-Cl-Ph 0 H H H H H 192 2-CF30-Ph 2,4-Cl2-Ph 0 H H H H H 193 3-CF30-Ph Ph 0 H H H H H 194 3-CF30-Ph 2-F-Ph 0 H H H H K 195 3-CF30-Ph 4-F-Ph 0 H H H H H 196 3-CF^O-Ph 2,4-F2-Ph 0 H H H H H 197 3-CF30-Ph 2-Cl-Ph 0 H H H H H 198 3-CF30-Ph 4-Cl-Ph 0 K H H H H 199 3-CF30-Ph 2,4-Cl2-Ph 0 H H H H H 200 4-CF30-Ph Ph 0 H H H H H 201 4-CF30-Ph 2-F-Ph 0 H H H H H 202 4-CF30-Ph 4-F-Ph 0 H H H H H 203 4-CF30-Ph 2,4-F2-Ph 0 H H H H H 204 4-CF30-Ph 2-Cl-Ph 0 H H H H H 33 ;V;:r-'"''5::""'-"',J""-• J ■ . ' 234 84 1 <D 34 Table 1 (Continued) EX' Mo. A B n R R1 R R3 R4 M.P.'C 205 4-CF^O-Ph 4-Cl-Ph 0 H H H H H 206 4-CF^O-Ph 2,4-Cl2-Ph 0 H H H H H 207 4-F-l-naphthyl 2-F-Ph 0 H H H H H 208 1-naphthyl 4-F-Ph 0 H H H H H 209 1-naphthyl 2,4-F2-Ph 0 H H H H H 210 1-naphthyl 2-Cl-Ph 0 H H H H H 211 2-Cl-l-naphthyl . 4-Cl-Ph 0 H H H . H H 212 1-naphthyl 2.4-Cl2-Ph 0 H H H H H 213 2-naphthyl 2-F-Ph 0 H H H K H 214 2-naphthyl 4-F-Ph 0 H H H H H 215 2-naphthyl 2,4-F2-Ph 0 H H H H K 216 2-naphthyl 2-C1 0 H H H H H 217 l-Cl-2-naphthyl 4-Cl-Ph 0 H H H H H 218 2-naphthyl 2,4-Cl2-Ph 0 H H H H H 219 2-thienyl Ph 0 H H H H H 220 2-thienyl 2-F-Ph 0 H H H H H 221 2-thienyl 4-F-Ph 0 H H H H H 222 2-thienyl 2,4-F,-Ph 0 H H H H H 223 2-thienyl 2-Cl-Ph 0 H H H H H 224 2-thienyl 4-Cl-Ph 0 H H H H H 225 2-thienyl 2,4-Cl2-Ph 0 H H H H H 226 3-thienyl Ph 0 H H H H H 227 3-thienyl 2-F-Ph 0 H H H H H 228 3-thienyl 4-F-Ph 0 H H H H H 229 3-thienyl 2,4-F2-Ph O H H H H H 230 3-thienyl 2-Cl-Ph 0 H H H H H 231 3-thienyl 4-Cl-Ph 0 H H H H H 232 3-thienyl 2,4-Cl2-Ph 0 H H H H H 104-106 34 234841 o C^/ 10 Table 1 (Continued) No.
A B n R si R! B! r! 233 2-Cl-3-thienyl Ph 0 H H H H H 234 2-Cl-3-thienyl 2-F-Ph 0 H H H H H 235 2-Cl-3-thienyl 2-Cl-Ph 0 H H H H H 236 -Cl-2-thienyl Ph 0 H H H H H 237 -Cl-2-thienyl 2-F-Ph 0 H H H H H 238 -Cl-2-thienyl 2-Cl-Ph 0 H H H H H 239 2,5-Cl2-3-thienyl Ph 0 H H H H H 240 2,5-Cl2-3-thienyl 2-F-Ph 0 H H H H H 241 2,5-Cl2-3-thienyl 4-F-Ph 0 H H H H H H.P."C 242 2,5-Cl2-3-thienyl 2,4-F2-Ph 0 H H H H H 243 2,5-Cl2-3-thienyl 2-Cl-Ph 0 H H H H H 244 2,5-Cl2-3-thienyl 4-Cl-Ph 0 H H H H H 245 2,5-Cl2-3-thienyl 2,4-Cl2-Ph 0 H H H H H 246 -bromo-2-thienyl Ph 0 H H H H H 247 -bromo-2-thienyl 2-F-Ph 0 H H H H H 248 -bromo-2-thienyl 4-F-Ph 0 H H H H H 249 -bromo-2-thienyl 2,4-F2-Ph 0 H H H H H 250 -bromo-2-thienyl 2-Cl-Ph 0 H H H H H 251 -bromo-2-thienyl 4-Cl-Ph 0 H H H H H 252 -bromo-2-thienyl 2,4-Cl2-Ph 0 H H H H H 253 2-pyridyl Ph 0 H H H H H 254 2-pyridyl 2-F-Ph 0 H H H H H 255 2-pyridyl 2-Cl-Ph 0 H H H H H 256 3-pyridyl Ph 0 H H H H H 257 3-pyridyl 2-F-Ph 0 H H H H H 258 3-pyridyl 2-Cl-Ph 0 H H H H H -iW«* r^-xiXh 234 36 Table 1 (Continued) Ex. No. n R R R2 R3 R4 M.P.*C 259 4-pyridyl Ph 0 H H H H H 260 4-pyridyl 2-F-Ph 0 H H H H H 261 4-pyridyl 2-Cl-Ph 0 H H H H H 262 5-Cl-2-pyridyl Ph 0 H H H H H 263 5-Cl-2-pyridyl 2-F-Ph 0 H H H H H 264 5-Cl-2-pyridyl 2-Cl-Ph 0 H H H H H 265 2-Cl-3-pyridyl Ph 0 H H H H H 266 2-Cl-3-pyridyl 2-F-Ph 0 H H H H H 267 2-Cl-3-pyridyl 4-F-Ph 0 H H H H H 268 2-Cl-3-pyridyl 2,4-F2-Ph 0 H H H H H 269 2-Cl-3-pyridyl 2-Cl-Ph 0 H H H H H 270 2-Cl-3-pyridyl 4-Cl-Ph 0 H H H H H 271 2-Cl-3-pyridyl 2,4-Cl2-Ph 0 H H H H H 272 3-Cl-2-pyridyl Ph 0 H H H H H 273 3-Cl-2-pyridyl 2-F-Ph 0 H H H H H 274 3-Cl-2-pyridyl 4-F-Ph 0 H H H H H 275 3-Cl-2-pyridyl 2,4-F2-Ph 0 H H H H H 276 3-Cl-2-pyridyl 2-Cl-Ph 0 H H H H H 277 3-Cl-2-pyridyl 4-Cl-Ph O H H H H H 278 3-Cl-2-pyridyl 2,4-Cl2-Ph O H H H H H 279 6-Cl-3-pyridyl Ph 0 H H H H K 280 6-Cl-3-pyridyl 2-F-Ph O H H H H H 281 6-Cl-3-pyridyl 4-F-Ph O H H H H H 282 6rCl-3-pyridyl 2,4-F2-Ph 0 H H H H H 283 6-Cl-3-pyridyl 2-Cl-Ph O K H H H H 284 6-Cl-3-pyridyl 4-Cl-Ph 0 H H H H H 285 6-Cl-3-pyridyl 2,4-Cl2-Ph O H H H H H 36 37 Table 1 (Continued) EX" 12 3 4 Wo. A B n R R_ R_ R_ R_ M.P.'C 286 Ph 4-F-Ph OH CH3 H H H 108-111 287 Ph 4-F-Ph OH F H H H 288 Ph 4-F-Ph OH Cl H H H 289 Ph 4-F-Ph OH Br H H H 290 Ph 4-F-Ph O -(CH2)2- H H H 291 Ph 4-F-Ph OH Ph H H H (oil)6 292 Ph 4-F-Ph O CH3 CH3 H H H 293 Ph 4-F-Ph OF F H H H 294 Ph 4-F-Ph 0 Cl Cl H H H 295 4-F-Ph 4-F-Ph OH CH3 H H H . 296 4-F-Ph 4-F-Ph OH F H H H 297 4-F-Ph 4-F-Ph OH Cl H H H 298 4-F-Ph 4-F-Ph OH Br H H H 20 299 4-F-Ph 4-F-Ph O -(CH^- H H H 300 4-F-Ph 4-F-Ph O CH, CH H H H 3 3 301 4-F-Ph 4-F-Ph OF F H H H 302 4-F-Ph 4-F-Ph 0 Cl Cl H H H 303 4-Cl-Ph 2,4-Cl2-Ph OH CH3 H H H 304 4-Cl-Ph 2,4-Cl2-Ph OH F H H H 305 4-Cl-Ph 2,4-Cl2-Ph OH Cl H H H 306 4-Cl-Ph 2,4-Cl2-Ph OH Br H H H 30 307 4-Cl-Ph 2,4-Cl2-Ph 0 -(CH^- H H H 308 4-Cl-Ph 2,4-Cl2-Ph 0 CH3 CH3 H H H 309 4-Cl-Ph 2,4-Cl2-Ph OF F H H H 310 4-Cl-Ph 2,4-Cl2-Ph 0 Cl Cl H H H 3 5 311 2-Cl-Ph 4-Cl-Ph OH CH3 H H H 312 2-Cl-Ph 4-Cl-Ph OH F H H H 37 r- - - • 234 8 c I r>; ; 'Urtkjr^ i ? ;, ; 38 Table 1 (Continued) Ex.
Mo. A B n R "R_ 313 2-Cl-Ph 4-Cl-Ph OH Cl 314 2-Cl-Ph 4-Cl-Ph OH Br 315 2-Cl-Ph 4-Cl-Ph 0 -(CH^- 316 2-Cl-Ph 4-Cl-Ph 0 CH3 CH3 H H H R! R! R4 M.P.-C H H H H H H H H H 317 2-Cl-Ph 4-Cl-Ph 0 F F H H H 318 2-Cl-Ph 4-Cl-Ph 0 Cl Cl H H H 319 4-F-Ph 4-F-Ph 0 H C2H5 H H H 320 4-F-Ph 4-F-Ph 0 H i"C3H7 H H H 321 4-F-Ph 4-F-Ph 0 H n-c4«9 H H H 322 4-F-Ph 4-F-Ph 0 H Ph H H K 323 4-F-Ph 4-F-Ph 0 CH3 t-CAH9 H H H 324 4-F-Ph 4-F-Ph 0 CH3 Ph H H H 325 4-F-Ph 4-F-Ph 0 H I H H H 326 4-F-Ph 4-F-Ph 0 CH3 F H H H 327 4-F-Ph 4-F-Ph 0 % Cl H H H 328 4-F-Ph 4-F-Ph 0 Br Br H H H 329 4-F-Ph 4-F-Ph 0 -(CH 2?3- K H H 330 4-F-Ph 4-F-Ph 0 -(CH 2}4" H H H 331 4-F-Ph 4-F-Ph 0 -(CH 2}5" H H H 332 4-F-Ph 4-F-Ph 0 -(CH 2}6~ H H H 333 4-CH3-Ph 4-F-Ph 0 H CH3 H H H 334 4-F-Ph 4-F-Ph 1 H CH3 H H H 335 4-Cl-Ph 4-F-Ph 4 H CH3 H H H 336 *"C4F9 4-F-Ph 0 H CH3 H H H 337 (ch3)2n 4-F-Ph 1 H ch3 H H H 338 -Cl-thio-phen-2-yl 4-F-Ph 0 H ch3 H h H 38 , _ . K;Joc-.'A- ww .atawrff-xv-ii tw.-vr^v - 1 r ^ \ n. 39 Table 1 (Continued) Ex. 2 2* Ho. A B n R R_ R R r' 339 2-Cl-thio- 4-F-Ph OH CH3 H H H phen-3-yl 340 1-imida- 4-F-Ph OH CH, H H H zoyl 3 341 1,2,4-tria- 4-F-Ph OH CH H H H zol-l-yl 342 5-chloro-2- 4-F-Ph OH CH3 H H H j pyridyl | 343 4-F-Ph n-C H OH CH, H H H .j ""493 ] 344 4-F-Ph t-C^Hg OH CH3 H H H \ i 345 4-F-Ph n-C,Fw OH CH_ H H H j , c - 4 9 3 I 15 | 346 4-CH -Ph 4-F-Ph OH F H H H G 347 4-F-Ph 4-F-Ph 1 H F H H H 348 4-Cl-Ph 4-F-Ph 4 H F H H H 349 n-C.Fft 4-F-Ph OH F H H H A 9 350 (CH3)2H 4-F-Ph 1 H F H H H 351 5-C1- 4-F-Ph OH F H H H thiophen- 2-yl 352 2-C1- 4-F-Ph OH F H H H 2 g thiophen- 2-yl 353 1-imida- 4-F-Ph OH F H H H royl 354 1,2,4- 4-F-Ph OH F H H H triazol- i-yi 355 5-C1-2- 4-F-Ph OH F H H H pyridyl 356 4-F-Ph 2-C4H9 OH F H H H 357 4-F-Ph £-C4H9 0 H F H H H 35 358 4-F-Ph £-C4F9 OH F H H H 39 40 Table 1 (Continued) EX' 12 3 4 Mo. A B n R R_ R_ R_ R_ M.P.'C 359 4-F-Ph 4-F-Ph 0 H H CH3 H H (oil)h 360 4-F-Ph 4-F-Ph 0 H H CH2CH-CH2 H H (oil)* 361 4-F-Ph 4-F-Ph 0 H H COCH3 H H (oil)J 1Q 362 4-F-Ph 4-F-Ph 0 H H C02CH3 H H 363 4-F-Ph 4-F-Ph 0 H H COMHO^ H H 164-167 364 4-F-Ph 4-F-Ph 0 H H CONH-nBu H H 365 4-F-Ph 4-F-Ph 0 H H CONHPh H H 366 4-F-Ph 4-F-Ph 0 H H CONH- H H 15 (4-F-Ph) 367 4-F-Ph 4-F-Ph O H H CON(CH3>2 H H 368 2-Cl-Ph 4-Cl-Ph 0 H H CH3 H H 369 2-Cl-Ph 4-Cl-Ph 0 H H CH2CH»CH2 H H 20 370 2-Cl-Ph 4-Cl-Ph O H H C0CH3 H H 371 2-Cl-Ph 4-Cl-Ph 0 H H C0„CH„ H H 2 3 372 2-Cl-Ph 4-Cl-Ph 0 H H C0NHCH.J H H 373 2-Cl-Ph 4-Cl-Ph 0 H H CONH-nBu H H 25 374 2-Cl-Ph 4-Cl-Ph O H H CONHPh H H 375 2-Cl-Ph 4-Cl-Ph O H H CONH- H H (4-F-Ph) 376 2-Cl-Ph 4-Cl-Ph 0 H H C0N(CH3)2 H H 377 4-Cl-Ph 2,4-Cl2-Ph 0 H H CH3 H H 378 4-Cl-Ph 2,4-Cl2-Ph O H H CH2CH=CH2 H H 379 4-Cl-Ph 2,4-Cl2-Ph 0 H H C0CH3 H H 380 4-Cl-Ph 2,4-Cl2-Ph O H H C02CH3 H H 381 4-Cl-Ph 2,4-Cl2-Ph 0 H H C0NHCH3 H H 382 4-Cl-Ph 2,4-Cl2-Ph O H H CONH-nBu H H 383 4-Cl-Ph 2,4-Cl2-Ph 0 H H CONHPh H H 40 234841 «W 41 Table 1 (Continued) EX- 12 3 4 No. A B n R R_ R R_ R_ H.P.'C 384 4-Cl-Ph 2,4-C1 -Ph 0 H H C0NH(4-F-Ph) H H I 385 4-Cl-Ph i 2,4-Cl2- •Ph 0 H H con(ch3)2 H H 386 Ph 4-F-Ph 0 H H CH3 H H 387 Ph 4-F-Ph 0 H H CHCH«*CH„ 2 2 H H 388 Ph 4-F-Ph 0 H H coch3 H H 389 Ph 4-F-Ph 0 H H co.ch, 2 3 H H 390 Ph 4-F-Ph 0 H H cotjhch3 H H 391 Ph 4-F-Ph 0 H H CONH-nBu H H 392 Ph 4-F-Ph 0 H H COHHPh H H 393 Ph 4-F-Ph 0 H H C0HH(4-F-Ph) H H 394 Ph 4-F-Ph 0 H H coh(ch3)2 H H 395 4-F-Ph 4-F-Ph 0 H H °2H5 H H 396 4-F-Ph 4-F-Ph 0 H H i"C3H7 H H 397 4-F-Ph 4-F-Ph 0 H H n-c^g H H 398 4-F-Ph 4-F-Ph 0 H H COC H 2 5 H H 399 4-F-Ph 4-F-Ph 0 H H CO-tC.H„ — 4 9 H H 400 4-F-Ph 4-F-Ph 0 H H COPh H H 401 4-F-Ph 4-F-Ph 0 H H COCH£Ph H H 402 4-F-Ph 4-F-Ph 0 H H conh2 H H 403 4-F-Ph 4-F-Ph 0 H H CONH-iC3H? H H 404 4-F-Ph 4-F-Ph 0 H H CONHCH2Ph H H 405 4-F-Ph 4-F-Ph 0 H H CON(CH3)Ph H H 41 ...-rv 234841 42 Table 1 (Continued) Ho. A B n R r]; R2 H.P.'C 406 4-F-Ph 4-F-Ph 0 H H CONH(4-Cl-Ph) H H 407 4-F-Ph 4-F-Ph 0 H H C0NH(4-CH3~Ph) H H 408 4-F-Ph 4-F-Ph 0 H H CONH(4-CH3-Ph) H H 409 4-F-Ph 4-F-Ph 0 H H CONH(3-CF3-Ph) H H 10 410 4-F-Ph 4-F-Ph 0 H H C0NH(4-HO2~Ph) H H 411 4-F-Ph 4-F-Ph 0 H H C0tm(2-CH3-Ph) H H 412 4-F-Ph 4-F-Ph 0 H H C0HH(2,4-F2-Ph) H H 413 4-F-Ph 4-F-Ph 0 H H C0HH(2,4-Cl2-Ph) H H 414 4-F-Ph 4-F-Ph 0 H H C0„C„He H H 2 2 5 415 4-F-Ph 4-F-Ph 0 H H C0„-nC H H H 2-49 416 4-F-Ph 4-F-Ph 0 H H CO -tC H„ H H 2-49 417 4-F-Ph 4-F-Ph 0 H H C02CH2Ph H H 418 4-F-Ph 4-F-Ph 0 H H C02Ph H H 419 4-F-Ph 4-F-Ph 0 H H CF2H H H 420 4-F-Ph 4-F-Ph 0 H H CH2CF3 H H 421 4-F-Ph 4-F-Ph O H H CH„CH.,CH_F H H 25 2 2 2 422 4-F-Ph 4-F-Ph 0 H H CH„CH„CH„CH.1Cl H H 2 2 2 2 423 Ph 2,4-F2-Ph 0 H H CH^CECH H H 424 Ph 4-Cl-Ph O H H CH^CECH H H 3Q 425 4-F-Ph 2-F-Ph 0 H H CH^CECH H H 426 4-F-Ph '4-F-Ph 0 H H CH^CECH H H 427 4-F-Ph 2,4-F2-Ph 0 H H CH^CECH H H 428 4-F-Ph 2-Cl-Ph 0 H H CH -CECH H H 2 429 2-Cl-Ph 2,4-F -Ph 0 H H CH„-C=CH H H 2 2 42 ■ «=sss; 23 484 1 43 Table 1 (Continued) r> rT: EX. Mo.
B n R R 430 2-Cl-Ph 4-Cl-Ph 431 4-Cl-Ph 2-F-Ph 0 H H CH2-C=CH 0 H H CH2-C=CH 432 4-Cl-Ph 2,4-F2-Ph 0 H H CH2-C=CH 433 4-F-Ph 4-F-Ph 1 H H H 10 434 4-F-Ph 4-F-Ph 2 H H H 435 4-F-Ph 4-F-Ph 3 H H H 436 4-F-Ph 4-F-Ph 4 H H H 437 2-Cl-Ph 4-Cl-Ph 1 H H H 438 2-Cl-Ph 4-Cl-Ph 2 H H H 15 439 2-Cl-Ph 4-Cl-Ph 3 H H H 440 2-Cl-Ph 4-Cl-Ph 4 H H H 441 4-Cl-Ph 2,4-Cl2-Ph 1 H H H R3 R< H H H H H H H H H H H H H H H H H H H H H H H H M.P.*C 43 ! v^i 44 Table 1 (Continued) Ex. No.
Tl R R1 R2 R3 R4 M.P.'C 442 4-Cl-Ph 2.4-Cl2.
-Ph 2 H H H H H 443 4-Cl-Ph 2,4-Cl2- -Ph 3 H H H H H 444 4-Cl-Ph 2,4-Cl2- -Ph 4 H H H H H 445 Ph 4-F-Ph 1 H H H H H 446 Ph 4-F-Ph 2 H H H H H 44 7 OH 4-Cl-Ph 1 H H H H H (oil)* 448 OH Ph 1 H H H H H 94-100 449 OH 2,4-Cl2-Ph 1 H H H H H 166-168 450 OH 4-F-Ph 1 H H H H H 115-116 451 OH 4-Br-Ph 1 H H H H H (foam)^" 452 OH 4-Ph-Ph 1 H H H H H 140-143 453 (CH3)2N 2.4-Cl2- Ph 1 H H H H H 104-107 454 (CH3)2N 4-F-Ph 1 H H H H H (oil)® 455 (CH3)2N 4-Br-Ph 1 H H H H H (oil)" 456 (CH3)2N 4-Ph-Ph 1 H H H H H (oil)° 457 1-imidazoyl 4-F-Ph 1 H H H H H 458 1-imidaroyl 4-F-Ph 2 H H H H H 459 1-imidaroyl 4-F-Ph 3 H H H H H 460 1-imidaroyl 4-F-Ph 4 H H H H H 461 lH-1,2,4- 4-F-Ph 1 H H H H H triazol-l-yl 462 1H-1,2,4— 4-F-Ph triarol-l-yl 463 1H-1,2,4— 4-F-Ph triarol-l-yl 464 1H-1,2,4- 4-F-Ph triazol-l-yl 465 1H-1,2,4— 2,4-Cl2-Ph 1 H H H triazol-l-yl 466 1H-1,2,4- 2,4-Cl2-Ph 2 H H H H triazol-l-yl 2 H H H H H 3 H H H H H 4 H H H H H H H H 44 234 84 1 4m^r:: ■-5:• ■"■•^•■■*mii*.*»,*.' .... I 234 84 1 G 10 45 Table 1 (Continued) EX- 12 3 4 Wo. A B n R R* R R R M.P.-C 467 1-imidazoyl 2,4-Cl2-Ph 1 H H H H H 468 1-piperidyl Ph 1 H H H H H 469 1-piperidyl 2-F-Ph 1 H H H H H 4 70 1-piperidyl 4-F-Ph 1 H H H H H 471 1-piperidyl 2.4-F2-Ph 1 H H H H H 472 1-piperidyl 2-Cl-Ph 1 H H H H H 473 1-piperidyl 4-Cl-Ph 1 H H H H H 474 1-piperidyl 2,4-Cl2-Ph 1 H H H H H 475 2,6-(CH3)2~l-inorpholinyl Ph 1 H H H H H 476 2,6-(CH3)2-l-morpholinyl 2-F-Ph 1 H H H H H 477 2,6-(CH3)2-l-morpholinyl 4-F-Ph 1 H H H H H 478 2,6-(CH3)2-l-morpholinyl 2,4-F2-Ph 1 H H H H H 479 2,6-(CH3)2-l-jnorpholinyl 2-Cl-Ph 1 H H H H H 480 2,6-(CH3)2-l-niorpholinyl 4-Cl-Ph 1 H H H H H 481 2,6-(CH3)2-l-xnorpholinyl 2,4-Cl2-Ph 1 H H H H K 482 4-CH^-l-piperazinyl Ph 1 H H H H H 483 4-CH3~l-piperazinyl 2-F-Ph 1HH H H H 484 4-CH^-l-piperazinyl 4-F-Ph 1 H H H H H 485 4-CH3-l-piperazinyl 2,4-F2-Ph 1 H H H H H 486 4-CH^-l-piperazinyl 2-Cl-Ph 1 H H H H H 487 4-CH^-l-piperazinyl 4-Cl-Ph 1 H H H H H 488 4-CH3~l-piperazinyl 2.4-Cl2-Ph 1 H H H H H 489 4-n-Bu-l-piperazinyl Ph 1 H H H H H 490 4-n-Bu-l-piperazinyl 2-F-Ph 1 H H H H H 45 ,,r ---- - - • ~~*Kn,4>*t*%G$$]!pr.
,-. -;:'.. ^MrTfnVY'r*1 vn..i.ftMmM».. wjfcww" •— vt. ..• - 234 84 1 46 Table 1 (Continued) C Ho. A B n R R1 R' 2 R3 R4 M.P.*C 491 4-n-Bu-l-piperazinyl 4-F-Ph 1 H H H H H 492 4-n-Bu-l-piperazinyl 2,4-F2-Ph 1 H H H H H 493 4-n-Bu-l-piperazinyl 2-Cl-Ph 1 H H H H H 494 4-n-Bu-l-piperazinyl 4-Cl-Ph 1 H H H H H 495 4-n-Bu-l-piperazinyl 2,4-Cl2-Ph i 1 H H H H H 496 4-acetyl-l-piperazinyl Ph 1 H H H H H 497 4-acetyl-l-piperazinyl 2-F-Ph 1 H H H H H 498 4-acetyl-l-piperazinyl 4-F-Ph 1 H H H H H 499 4-acetyl-l-piperazinyl 2,4-F2-Ph 1 H H H H H 500 4-acetyl-l-piperazinyl 2-Cl-Ph 1 K H H H H 501 4-acetyl-l-piperazinyl 4-Cl-Ph 1 H H H H H 502 4-acetyl-l-piperazinyl 2,4-Cl2-Ph 1 H H H H H 503 2-(2-pyridyl)-Ph 4-F-Ph 0 H H H H H 504 2-(3-pyridyl)-Ph 4-F-Ph 0 H H H H H 505 2-(4-pyridyl)-Ph 4-F-Ph 0 H H H H H 506 3-(2-pyridyl)-Ph 4-F-Ph 0 H H H H H 507 3-(3-pyridyl)-Ph 4-F-Ph 0 H H H H H 508 3-(4-pyridyl)-Ph 4-F-Ph 0 H H H H H 509 4-(2-pyridyl)-Ph 4-F-Ph 0 H H H H H 510 4-(3-pyridyl)-Ph 4-F-Ph 0 H H H H H 511 4-(4-pyridyl)-Ph 4-F-Ph 0 H H H H H 512 2-(lH-l,2,4-triazol-l-yl)- ■Ph 4-F-Ph 0 H H H H H 513 3-(lH-l,2,4-triazol-l-yl)- •Ph 4-F-Ph 0 H H H H H 514 4-(lH-l,2,4-triazol-l-yl)- Ph 4-F-Ph 0 H H H H H 515 2-(imidazol-l-yl)-Ph 4-F-Ph 0 H H H H H 516 3-(imidazol-l-yl)-Ph 4-F-Ph 0 H H H H H 517 4-(imidazol-l-yl)-Ph 4-F-Ph 0 H H H H H 518 2-(4-methylpiperazin-l-yl) -Ph 4-F-Ph 0 H H H K H 46 234841 47 Table 1 (Continued) EX" 12 3 4 No. A B n R R R R R H.P.'C 519 3-(4-methylpiperazin-l-yl)-Ph 4-F-Ph 0 H H H H H 520 4-(4-methylpiperazin-l-yl)-Ph 4-F-Ph 0 H H H H H 521 2-(4-acetylpiperazin-l-yl)-Ph 4-F-Ph 0 H H H H H 522 3-(4-acetylpiperazin-l-yl)-Ph 4-F-Ph 0 H H H H H 523 4-(4-acetylpiperazin-l-yl)-Ph 4-F-Ph 0 H H H H H 524 2-(2-pyridyl)-Ph 2,4-F2-Ph 0 H H H H H 525 2-(3-pyridyl)-Ph 2,4-F2-Ph 0 H H H H H 526 2-(4-pyridyl)-Ph 2,4-F2-Ph 0 H H H H H 527 3-(2-pyridyl)-Ph 2,4-F2-Ph 0 H H H K H 528 3-(3-pyridyl)-Ph 2,4-F2-Ph 0 H H H H H 529 3-(4-pyridyl)-Ph 2,4-F2-Ph 0 H H H H H 530 4-(2-pyridyl)-Ph 2,4-F2-Ph 0 H H H H H 531 4-(3-pyridyl)-Ph 2,4-F2-Ph 0 H H K H H 532 4-(4-pyridyl)-Ph 2,4-F2-Ph 0 H H H H H 533 2-(lH-l,2,4-triazol-l-yl)-Ph 2,4-F2-Ph 0 H H H H H 534 3-(1H-1,2,4-triazol-l-yl)-Ph 2.4-F2-Ph 0 H H H H H 535 4-(lH-l,2,4-triazol-l-yl)-Ph 2,4-F2-Ph 0 H H H H H 536 2-(imidazol-l-yl)-Ph 2,4-F2-Ph 0 H H H H H 537 3-(imidazol-l-yl)-Ph 2,4-F2-Ph 0 H H H H H 538 4-(imidazol-l-yl)-Ph 2.4-F2-Ph 0 H H H H H 539 2-(4-methylpiperazin-2-yl)-Ph 2,4-F2-Ph 0 H H H H H 540 3-(4-methylpiperazin-2-yl)-Ph 2,4-F2-Ph 0 H H H H H 541 4-(4-methylpiperazin-2-yl)-Ph 2,4-F2-Ph 0 H H H H H ■ of o n\ w 4y& W 234 84 1 48 Table 1 (Continued) Ex. Wo. n R £ r! R? r1 M.P.-c 542 2-(4-acetylpiperazin-l-yl)-Ph 2,4-F2~Ph 0 H H H K H 543 3-(4-acetylpiperazin-l-yl)-Ph 2,4-F2~Ph 0 H H H H H 544 4-(4-acetylpiperazin-l-yl)-Ph 2,4-F2~Ph 0 H H H H H 545 2-Cl-3-(3-pyridyl)-Ph 2,4-F2-Ph 0 H H H H H 546 2-(2-pyridyl)-Ph 4-Cl-Ph 0 K H H H H 547 2-(3-pyridyl)-Ph 4-Cl-Ph 0 H H H H H 548 2-(4-pyridyl)-Ph 4-Cl-Ph 0 H H H H H 549 3-(2-pyridyl)-Ph 4-Cl-Ph 0 H H H H H 550 3-(3-pyridyl)-Ph 4-Cl-Ph 0 H H H H H 551 3-(4-pyridyl)-Ph 4-Cl-Ph 0 K H H H H 552 4-(2-pyridyl)-Ph 4-Cl-Ph 0 H H H H H 553 4-(3-pyridyl)-Ph 4-Cl-Ph 0 H H H H H 554 4-(4-pyridyl)-Ph 4-Cl-Ph 0 H H H H H 555 2-(lH-l,2,4-triazol-l-yl)-Ph 4-Cl-Ph 0 H H H H H 556 3-(lH-l,2,4-triazol-l-yl)-Ph 4-Cl-Ph 0 H H H H H 557 4-(lH-l,2,4-triazol-l-yl)-Ph 4-Cl-Ph 0 H H H H H 558 2-(imidazol-l-yl)-Ph 4-Cl-Ph 0 H H H H H 559 3-(imidazol-l-yl)-Ph 4-Cl-Ph 0 H H H H H 560 4-(imidazol-l-yl)-Ph 4-Cl-Ph 0 H H H H H 561 2-(4-methylpiperazin-l-yl)-Ph 4-Cl-Ph 0 H H H H H 562 3-(4-methylpiperazin-l-yl)-Ph 4-Cl-Ph 0 H H H H H 563 4-(4-me thylp iperaz in-l-yl)-Ph 4-Cl-Ph 0 H H H H H 564 2-(4-acetylpiperazin-l-yl)-Ph 4-Cl-Ph 0 H H H H H 565 3-(4-acetylpiperazin-l-yl)-Ph 4-Cl-Ph 0 H H H H H 566 4-(4-acetylpiperazin-l-yl)-Ph 4-Cl-Ph 0 H H H H H 567 2-Cl-3-(3-pyridyl)-Ph 4-Cl-Ph 0 H H H H H 568 2-(2-pyridyl)-Ph 2,4-Cl2-Ph 0 H H H H H 569 2-(3-pyridyl)-Ph 2,4-Cl2-Ph 0 H H H H H 570 2-(4-pyridyl)-Ph 2,4-Cl2-Ph 0 H H H H H 48 . w—i, ji u .smiM»B8gBgiMg«frjaa^^ ;£$..-.. !' n 234 84 1 H) 10 i 15 49 Table 1 (Continued) No^. A B n R R1 R2 R3 R4 M.P.'C 571 3-(2-pyridyl)-Ph 2,4-Cl2-Ph 0 H H H H H 572 3-(3-pyridyl)-Ph 2,4-Cl2-Ph 0 H H H H H 573 3-(4-pyridyl)-Ph 2,4-Cl2-Ph 0 H H H H H 574 4-(2-pyridyl)-Ph 2,4-Cl2-Ph 0 H H H H H 575 4-(3-pyridyl)-Ph 2,4-Cl2-Ph 0 H H H H H 576 4-(4-pyridyl)-Ph 2,4-Cl2-Ph 0 H H H H H 577 2-(lH-l,2,4-triazol-l-yl)- -Ph 2,4-Cl2-Ph 0 H H H H H 578 3-(lH-l,2,4-triazol-l-yl)- ■Ph 2,4-Cl2-Ph 0 H H H H H 579 4-(lH-l,2,4-triazol-l-yl)- •Ph 2.4-Cl2-Ph 0 H H H H H 580 2-(imidazol-l-yl)-Ph 2,4-Cl2-Ph 0 H H H H H 581 3-(imidazol-l-yl)-Ph 2.4-Cl2-Ph 0 H H H H H 582 4-(imidazol-l-yl)-Ph 2,4-Cl2-Ph 0 H H H H H 583 2-(4-methylpiperazin-l-yl) -Ph 2,4-Clj-Ph 0 H H H H H 584 3-(4-methylpiperazin-l-yl) -Ph 2,4-Cl2-Ph 0 H H H H H 585 4-(4-methylpiperazin-l-yl) -Ph 2,4-Cl2-Ph 0 H H H H H 586 2-(4-acetylpiperazin-l-yl)' -Ph 2,4-Cl2-Ph 0 H H H H H 587 3-(4-acetylpiperazin-l-yl)' -Ph 2,4-Cl2-Ph 0 H H H H H 588 4-(4-acetylpiperazin-l-yl)- -Ph 2,4-Cl2-Ph 0 H H H H H 589 2-Cl-3-(3-pyridyl)-Ph 2,4-Cl2-Ph 0 H H H H H 590 3-(morpholin-l-yl)-Ph 2,4-F2-Ph 0 H H H H H 591 3-(2,6-dimethy1-morpholin-l-yl)-Ph 2,4-F2-Ph 0 H H H H H 592 4-(n-butyl-piperazin-l-yl)- -Ph 2,4-F2-Ph 0 H H H H H 593 4-(piperidin-l-yl)-Ph 2,4-F -Ph 0 H H H H H 49 SJWww®8KS^,sa^^«-W£;i;,;?x^ ■K ^ 234 84 1 w& 50 Table 1 (Continued) O Ex. is No.
A B n R R i R I *1 M.P.-C 594 Ph 2-F-Ph 0 H H H H H (oil)P (HCl salt 190-195) | 595 Ph 3-F-Ph 0 H H H H H 596 Ph 2-Cl-Ph 0 H H H H H 78-80 | 597 Ph 3-Cl-Ph 0 H H H H H | 598 Ph 4-Br-Ph 0 H H H H H 92-95 i i 599 Ph 4-I-Ph 0 H H H H H 1 600 Ph 3,4-F2-Ph 0 H H H H H i 601 Ph 3,4-Cl2-Ph 0 H H H H H i 602 Ph 2,6-Cl2-Ph 0 H H H H H , 603 Ph 3,5-Cl2-Ph 0 H H H H H 142-144 604 Ph 2-Cl-(4-F)-Ph 0 H H H H K 605 Ph 3-Cl-(4-F)-Ph 0 H H H H H 119-124 (dec.) 606 Ph 2,4,6-Cl3-Ph 0 H H H H H 607 Ph 2-F-(4-C1)-Ph 0 H H H H H 608 Ph Ph 0 H H H H H 130-133 609 Ph 4-CH3-Ph 0 H H H H H j ■ 610 Ph 3-CH3-Ph 0 H H H H H 611 Ph 2-CH3-Ph 0 H H H H H 160.5-163 612 Ph 2-CF3-Ph 0 H H H H H 613 Ph 3-CF3-Ph 0 H H H H H 614 Ph 2-Cl-3-thienyl 0 H H H H H 615 Ph 2-F-(4-CF3)-Ph 0 H H H H H 50 1 i O J 234 84 1 51 Table 1 (Continued) i Ex.
Wo. A B n R R^ R^ R^ R^ H.P."C 616 Ph 4-CH30-Ph 0 H H H H H 617 Ph 5-Cl-2-pyridyl 0 H H H H H 618 Ph 5-Cl-2-thienyl 0 H H H H H 88-90 619 Ph -~C4H9 0 H H H H H 1Q 620 2-Cl-Ph 2-F-Ph 0 H H H H H 118-119 621 2-Cl-Ph 3-F-Ph 0 H H H H H 622 2-Cl-Ph 2-Cl-Ph 0 H H H H H 149-150 623 2-Cl-Ph 3-Cl-Ph 0 H H H H H 624 2-Cl-Ph 4-Br-Ph 0 H H H H H 151-152 625 2-Cl-Ph 4-I-Ph 0 H H H H H 626 2-Cl-Ph 3,4-F2-Ph 0 H H H H H 627 2-Cl-Ph 3,4-Cl2-Ph 0 H H H H H 122-123.5 628 2-Cl-Ph 2,6-Cl2-Ph 0 H H H H H 629 2-Cl-Ph 2-C1-(4-F)-Ph 0 H H H H H 630 2-Cl-Ph 2,4,6-Cl^-Ph 0 H H H H H 631 2-Cl-Ph 2-F-(4-Cl)-Ph 0 H H H H H 632 2-Cl-Ph Ph 0 H H H H H 633 2-Cl-Ph 4-CH^-Ph 0 H H H H H 634 2-Cl-Ph 3-CH3-Ph 0 H H H H H 635 2-Cl-Ph 2-CH3-Ph 0 H H H H H 636 2-Cl-Ph 2-CF3-Ph 0 H H H H H 637 2-Cl-Ph 3-CF3-Ph 0 H H H H H 638 2-Cl-Ph 2-F-(4-CF3)-Ph 0 H H H H H 639 2-Cl-Ph 4-CH30-Ph 0 H H H H H 640 2-Cl-Ph 5-Cl-2-pyridyl 0 H H H H H 51 - csiftr: 2 3 4 8 4 1 52 Table 1 (Continued) EX. Ho.
A B n R R! si si s! H.P.-C 641 2-Cl-Ph -Cl-2-thienyl 0 H H H H H 642 2-Cl-Ph 2-Cl-3-thienyl 0 H H H H H 643 2-Cl-Ph £-C4H9 0 H H H H H 644 4-F-Ph 2-F-Ph 0 H H H H H 96-97 645 4-F-Ph 3-F-Ph 0 H H H H H 646 4-F-Ph 2-Cl-Ph 0 H H H K H 116-119 647 4-F-Ph 3-Cl-Ph 0 H H H K H 648 4-F-Ph 4-Br-Ph 0 H H H H H 114-116 649 4-F-Ph 4-I-Ph 0 H H H H H 650 4-F-Ph 3,4-F2-Ph 0 H H H H H 651 4-F-Ph 3,4-Cl2-Ph 0 H H H H H 98-99 652 4-F-Ph 2,6-Cl2-Ph 0 H H H H H 653 4-F-Ph 2-Cl-(4-F)-Ph 0 H H H H H 654 4-F-Ph 2,4,6-Cl3-Ph 0 H H H H H 655 4-F-Ph 2-F-(4-C1)-Ph 0 H H H H H 656 4-F-Ph Ph 0 H H H H H 124-125 657 4-F-Ph 4-Ph-Ph 0 H H H H H 116-119 658 4-F-Ph 4-CH3-Ph 0 H H H H H 659 4-F-Ph 2-CH3-Ph 0 H H H H H 660 4-F-Ph 2-CF3-Ph 0 H H H H H 661 4-F-Ph 3-CF -Ph 0 H H H H H 3 662 4-F-Ph 2-F-(4-CF3)-Ph 0 H H H H H 663 4-F-Ph 4-CH30-Ph 0 H H H H H 664 4-F-Ph -Cl-2-pyridyl 0 H H H H H 665 4-F-Ph -Cl-2-thienyl 0 H H H H H 666 4-F-Ph 2-Cl-3-thienyl 0 H H H H H 145-147 145-149 121-122 112-114 114-115 52 msmm . J'."?"? 1>./,IL£S-.VV.» .. . 234 84 1 53 /O. o Table 1 (Continued) Ex.
Mo. A B n R R1 si si s! M.P.-C 667 4-F-Ph i-C3H7 0 H H K H H 74-75 668 4-F-Ph C2H5 0 H H H H H (oil)q 669 4-Cl-Ph 2-F-Ph 0 H H H H H 130-131 670 4-Cl-Ph 3-F-Ph 0 H H H H H 671 4-Cl-Ph 2-Cl-Ph 0 H H H H H 137-139 672 4-Cl-Ph 3-Cl-Ph 0 H H H H H 673 4-Cl-Ph 4-Br-Ph 0 H H H H H 121-123 674 4-Cl-Ph 4-I-Ph 0 H H H H H 675 4-Cl-Ph 3,4-Cl2-Ph 0 H H K H H 107-198 676 4-Cl-Ph 2,6-Cl2-Ph 0 H H H H H 677 4-Cl-Ph 2-Cl-(4-F)-Ph 0 H H H H H 678 4-Cl-Ph 2,4,6-Cl3-Ph 0 H H H H H 679 4-Cl-Ph 2-F-(4-Cl)-Ph 0 H H H H H 680 4-Cl-Ph Ph 0 H H H H H 681 4-Cl-Ph 4-CH3-Ph 0 H H H H H 682 4-Cl-Ph 3-CH3-Ph 0 H H H H H 683 4-Cl-Ph 2-CH3-Ph 0 H H H H H 684 4-Cl-Ph 2-CF3-Ph 0 H H K H H 685 4-Cl-Ph 3-CF3-Ph 0 H H H H H 103-104 686 4-Cl-Ph 2-F-(4-CF3)-Ph 0 H H H H H 687 4-Cl-Ph 4-CH30-Ph 0 H H H H H 688 4-Cl-Ph -Cl-2-pyridyl 0 H H H H H 689 4-Cl-Ph -Cl-2-thienyl 0 H H H H H 690 4-Cl-Ph 2-Cl-3-thienyl 0 H H H H H 53 54 Table 1 (Continued) 234 84 1 Ex.
No. n Q 691 4-Cl-Ph 692 4-F-Ph 693 4-F-Ph 10 694 4-F-Ph 695 4-F-Ph 696 4-F-Ph 697 4-F-Ph 15 698 4-F-Ph 699 4-F-Ph 700 4-F-Ph 701 4-F-Ph 702 4-F-Ph 20 703 4-F-Ph 704 4-F-Ph 705 4-F-Ph 706 4-C2H5-Ph 707 4-(n-Bu0)-Ph 708 2-CH3S02-imidazol-l-yl 709 5-CH3-l,2,4-30 triazol-l-yl 710 "C6F13 711 "C8F17 —-C4H9 X C6H4-4F Jb-butyl n-hexyl n-heptyl n R R1 R2 R3 R* M.P.'C O H H H H H 0 H H H H H 0 H H H H H 0 H H H H H 0 H H H H H 2,4-(CH3)2-Ph 0 H H H H H 148-149 -C F 6 13 -C F 8 17 4-pyridyl 2-pyridyl 2-thienyl 4-n-Bu-Ph 4-n-BuO-Ph 0 H H H H H 0 H H H H H 0 H H H H H 175-178 0 H H H H H 0 H H H H H 0 H H H H H 0 H H H H H -CF -pyrid- 0 H H H H H 2-yl -HeS02-2- thienyl 4-F-Ph 4-F-Ph 4-F-Ph 4-F-Ph 4-F-Ph 4-F-Ph 712 2-C1-3-(3-pyridyl)-Ph 4-F-Ph 0 H H H H H 0 H H H H H 0 H H H H H 0 H H H H H O H H H H H O H H H H H O H H H H H 0 H H H H H 54 234 84 1 55 Table 1 (Continued) Ex. o o Ho. A B n R R 0 H H is ill H.P.-C 713 Z-CF^-imidazol-l-yl 4-F-Ph H H H 714 4-(i-PrO)-Ph 4-F-Ph 0 H H H H H 715 4-I-Ph 4-F-Ph 0 H H H H H 716 3,4-F2-Ph 4-F-Ph 0 H H H H K 717 3,4-Cl2-Ph 4-F-Ph 0 H H H H H 718 2,6-Cl2-Ph 4-F-Ph 0 H H H H H 719 2-Cl-(4-F)-Ph 4-F-Ph 0 H H H H H 720 2,4,6-Cl3-Ph 4-F-Ph 0 H H H H H 721 4-CH3-Ph 4-F-Ph 0 H H H H H 119-120 722 3-CH3-Ph 4-F-Ph 0 H H H H H 723 2-CH^-Ph 4-F-Ph 0 H H H H H 724 2-CF3-Ph 4-F-Ph 0 H H H H H 110-112 725 3-CF3-Ph 4-F-Ph 0 H H H H H 106-108 726 4-CH30-Ph 4-F-Ph 0 H H H H H 109-111 727 2,3-Cl2-Ph 4-F-Ph 0 H H H H H 728 3,5-Cl2-Ph 4-F-Ph 0 H H H H H 729 2,5-Cl2-Ph 4-F-Ph 0 H H H H H 730 3-Br-Ph 4-F-Ph 0 H H H H H 731 4-Et0-Ph 4-F-Ph 0 H H H H H 732 2,4-(CH3)2-Ph 4-F-Ph 0 H H H H H 733 2,4,6-(CH3)3-Ph 4-F-Ph 0 H H H H H 734 4-Ph-Ph 4-F-Ph 0 H H H H H 735 5-Cl-2-thienyl 4-F-Ph 0 H H H H H 736 2-Cl-3-thienyl 4-F-Ph 0 H H H H H jM;SKS;a'5a«ss5ss®a» 55 234 84 1 56 Table 1 (Continued) G r>.
V - •'; < No. A B n E £ is 2 _ R_ ial 737 1-imidaroyl 4-F-Ph 0 H H H H H 738 1H-1,2,4-triazoyl 4-F-Ph 0 H H H H H 739 2-pyridyl 4-F-Ph 0 H H H H H 740 5-Cl-pyrid-2-yl 4-F-Ph 0 H H H H H 741 3-pyridyl 4-F-Ph 0 H H H H H 742 4-pyridyl 4-F-Ph 0 H H H H H 743 n-C.F,. - 4 9 4-F-Ph 0 H H H H H 744 4-I-Ph 2,4-Cl2-Ph 0 H H H H H 745 3,4-F2-Ph 2,4-Cl2-Ph 0 H H H H H 746 3,4-Cl2-Ph 2,4-Cl2-Ph 0 H H H H H 747 2,6-Cl2-Ph 2,4-Cl2-Ph 0 H H H H H 748 2-Cl-(4-F)-Ph 2,4-Cl2-Ph 0 H H H H H 749 2,4,6-Cl3-Ph 2.4-Cl2-Ph 0 H H H H H 750 4-CH3-Ph 2,4-Cl2-Ph 0 H H H H H 751 3-CH3-Ph 2,4-Cl2-Ph 0 H H H H H 752 2-CH3-Ph 2,4-Cl2-Ph 0 H H H H H 753 2-CF3-Ph 2,4-Cl2-Ph 0 H H H H H 754 3-CF3-Ph 2,4-Cl2-Ph 0 H H H H H 755 4-CH30-Ph 2,4-Cl2-Ph 0 H H H H H 756 2,3-Cl2-Ph 2,4-Cl2-Ph 0 H H H H H 757 3,5-Cl2-Ph 2,4-Cl2-Ph 0 H H H H H 758 2,5-Cl2-Ph 2,4-Cl2-Ph 0 H H H H H 759 3-Br-Ph 2,4-Cl2-Ph 0 H H H H H 760 4-EtO-Ph 2.4-Cl2-Ph 0 H H H H H 56 234841 n & 57 Table 1 (Continued) C.X.
No. A B n E K ii 2 _ K is: 761 2,4-(CH3)2-Ph 2,4-Cl2 -Ph 0 H H H H K 762 2,4,6-(CH3)3-Ph 2,4-Cl2.
-Ph 0 H H H H H 763 4-Ph-Ph 2,4-Cl^ -Ph 0 H H H H H 764 5-Cl-2-thienyl 2,4-Cl2- -Ph 0 H H H H H 765 2-Cl-3-thienyl 2.4-Cl2- -Ph 0 H H H H H 766 1-imidaxoyl 2.4-Cl2- -Ph 0 H H H H H 767 1H-1,2,4-triazoyl- -1-yl 2.4-ci2- -Ph 0 H H h h h 768 2-pyridyl 2.4-Cl2- -Ph 0 H H h h h 769 5-Cl-pyrid-2-yl 2,4-Cl2- -Ph 0 H H h h h 770 3-pyridyl 2.4-Cl2- ■Ph 0 H H h h h 771 4-pyridyl 2,4-Cl2- ■Ph 0 H H h h h 772 s-C4F9 2,4-Cl2- Ph 0 H H h h h 773 4-I-Ph 4-Cl-Ph 0 H H H H H 774 3,4-F2-Ph 4-Cl-Ph 0 H H H H H 775 3,4-Cl2-Ph 4-Cl-Ph 0 H H H H H 776 2,6-Cl2-Ph 4-Cl-Ph 0 H H H H H 777 2-C1-(4-F)-Ph 4-Cl-Ph 0 H H H H H 778 2,4,6-Cl3-Ph 4-Cl-Ph 0 H H H H H 779 4-CH3-Ph 4-Cl-Ph 0 H H H H H 780 3-CH3-Ph 4-Cl-Ph 0 H H H H H 781 2-CH3-Ph 4-Cl-Ph 0 H H H H H 782 2-CF3-Ph 4-Cl-Ph 0 H H H H H 783 3-CF -Ph 4-Cl-Ph 0 H H H H H 57 234 84 1 58 Table 1 (Continued) Ex.
Mo. n R R1 R2 R3 R4 M.P.-C n.
V„C 784 4-CH30-Ph 4-Cl-Ph 0 H H H H H 785 2,3-Cl2-Ph 4-Cl-Ph 0 H H H H H 786 3,5-Cl2-Ph 4-Cl-Ph 0 H H H H H 787 2,5-Cl2-Ph 4-Cl-Ph 0 H H H H H 788 3-Br-Ph 4-Cl-Ph 0 H H H H H 789 4-EtO-Ph 4-Cl-Ph 0 H H H H H 790 2,4-(CH3)2-Ph 4-Cl-Ph 0 H H H H H 791 2.4,6-(CH3)3-Ph 4-Cl-Ph 0 H H H H H 792 4-Ph-Ph 4-Cl-Ph 0 H H H H H 793 5-Cl-2-thienyl 4-Cl-Ph 0 H H H H H 794 2-Cl-3-thienyl 4-Cl-Ph 0 H H H H H 795 1-iroidazoyl 4-Cl-Ph 0 H H H H H 796 1H-1,2,4-triazoy1- -1-yl 4-Cl-Ph 0 H H H H H 797 2-pyridyl 4-Cl-Ph 0 H H H H H 798 5-Cl-pyrid-2-yl 4-Cl-Fh 0 H H H H H 799 3-pyridyl 4-Cl-Ph 0 H H H H H 800 4-pyridyl 4-Cl-Ph 0 H H H H H 801 n-C.F. - 4 9 4-Cl-Ph 0 H H H H H 802 4-I-Ph 2,4-F2-Ph 0 H H H H H 803 3,4-F2-Ph 2,4-F2-Ph 0 H H H H H 804 3,4-Cl2-Ph 2,4-F2-Ph 0 H H H H H 805 2,6-Cl2-Ph 2,4-F2-Ph 0 H H H H H 806 2-Cl-(4-F)-Ph 2,4-F2-Ph 0 H H H H H 807 2,4,6-Cl3-Ph 2,4-F2-Ph 0 H H H H H 808 4-CH3-Ph 2,4-F2-Ph 0 H H H H H 129-130.5 58 a™ 234 84 1 59 Table 1 (Continued) o Ex.
Ko. A 1 2 3 4 n R R R R R M.P.*C 809 3-CH3-Ph 2,4-F2-Ph 0 H H H H H 810 2-CH^-Ph 2,4-F2-Ph 0 H H H H H 811 2-CF3-Ph 2,4-F2-Ph 0 H K H H H 812 3-CF3-Ph 2,4-F2-Ph 0 H H H H H 813 4-CH.jO-Ph 2,4-F2-Ph 0 H H H H H 814 2,3-Cl2-Ph 2,4-F2-Ph 0 H H H H H 815 3,5-Cl2-Ph 2,4-F2-Ph 0 H H H H H 816 2,5-Cl2-Ph 2,4-F2-Ph 0 H H H H H 817 3-Br-Ph 2,4-F2-Ph 0 H H H H H 818 4-EtO-Ph 2,4-F2-Ph 0 H H H H H 819 2,4-(CH3)2-Ph 2,4-F2-Ph 0 H H H H H 820 2,4,6-(CH3)3-Ph 2,4-F2-Ph 0 H H K H H 821 4-Ph-Ph 2.4-F2-Ph 0 H H H H H 822 5-Cl-2-thienyl 2.4-F2-Ph 0 H H H H H 823 2-Cl-3-thienyl 2,4-F2-Ph 0 H H H H H 824 1-imidazoyl 2,4-F2-Ph 0 H H H H H 825 1H-1,2,4-triazoyl-l-yl 2,4-F2-Ph 0 H H H H H 826 2-pyridyl 2,4-F2-Ph 0 H H H H H 827 5-Cl-pyrid-2-yl 2,4-F2-Ph 0 H H H H H 828 3-pyridyl 2,4-F2-Ph 0 H H H H H 829 4-pyridyl 2,4-F2-Ph 0 H H H H H 830 n-C.F„ ~ 4 9 2,4-F2-Ph 0 H H H H H 59 60 Table 1 (Continued) C *53) Ex. Ko.
A B USE.1 0 H H R? ' 3 ; R: i i . R 831 2-F-Ph 4-Br-Ph H H H 832 3-F-Ph 4-Br-Ph 0 H H H H H 833 3-Cl-Ph 4-Br-Ph 0 H H H H H 834 4-Br-Ph 4-Br-Ph 0 H H H H H 835 2,4-F2-Ph 4-Br-Ph 0 H H H H H 836 2,4-Cl2-Ph 4-Br-Ph 0 H H H H H 837 2-CF3-Ph 4-Br-Ph 0 H H H H H 838 3-CF^-Ph 4-Br-Ph 0 H H H H H 839 4—CF -Ph 4-Br-Ph 0 H H H H H 3 840 2-F-Ph 4-I-Ph 0 H H H H H 841 3-F-Ph 4-I-Ph 0 H H H H H 842 3-Cl-Ph 4-I-Ph 0 H H H H H 843 4-Br-Ph 4-I-Ph 0 H H H H H 844 2,4-F2-Ph 4-I-Ph 0 H H H H H 845 2,4-Cl2-Ph 4-I-Ph 0 H H H H H 846 2-CFj-Ph 4-I-Ph 0 H H H H H 847 3-CF3-Ph 4-I-Ph 0 H H H H H 848 4-CF3-Ph 4-I-Ph 0 h h H H H 849 2-F-Ph 2-CH3-Ph 0 h h H H H 850 3-F-Ph 2-CH3-Ph 0 h h H H H 851 3-Cl-Ph 2-CH3-Ph 0 H H H H H 852 4-Br-Ph 2-CH3-Ph 0 H H H H H 853 2,4-F2-Ph 2-CH3-Ph 0 H H H H H 854 2,4-Cl2-Ph 2-CH3-Ph 0 H H H H H 60 ■■1 ■ 234 84 1 61 Table 1 (Continued) O n •w--1 Ex.
No.
B n R R1 R2 R3 R4 H.P.'C 855 2-CF3-Ph 2-CH3-Ph 0 H H H H H 856 3-CF3-Ph 2-CH3-Ph 0 H H H H H 857 4-CF3-Ph 2-CH3-Ph 0 H H H H H 858 4-(4-F-Ph)-Ph 4-F-Ph 0 H H H H H 859 4-(2-Cl-Ph)-Ph 4-Cl-Ph 0 H H H H H 860 3-(3-CF -Ph)-Ph 2.4-F -Ph 0 H H H H H 861 3-(2,4-F2-Ph)-Ph 862 2,4-F2-Ph 863 4-CH3-Ph 864 2-CF3-Ph 865 3-CF3-Ph 866 4-CF3-Ph 867 2-F-Ph 868 3-F-Ph 869 3-Cl-Ph 870 4-Br-Ph 871 2,4-F2-Ph 872 2,4-Cl2-Ph 873 2-CF3-Ph 874 3-CF3-Ph 875 4-CF3-Ph 876 Ph 877 2-F-Ph 2,4-Cl2-Ph 4-CH3-Ph 4-CH3-Ph 4-CH3-Ph 4-CH3-Ph 4-CH3-Ph 4-CH30-Ph 4-CH30-Ph 4-CH30-Ph 4-CH30-Ph 4-CH30-Ph 4-CH30-Ph 4-CH30-Ph 4-CH30-Ph 4-CH30-Ph 2-CH30-Ph 2-CH30-Ph 0 H H H H H 0 H H H H H 0 H H H H H 178-181.5 0 H H H H H 0 H H H H H 0 H H H H H 0 H H H H H 0 H H H H H 0 H H H H H 0 H H H H H 0 H H H H H 0 H H H H H 0 H H H H H 0 H H H H H 0 H H H H H 0 H H H H H 0 H H H H H 61 234 8 62 Table 1 (Continued) O Ex.
NO. 878 3-F-Ph B 2-CH30-Ph H E ii El M.P.*C 0 H H H H H o 879 4-F-Ph 880 2,4-F2-Ph 881 2-Cl-Ph 882 3-Cl-Ph 883 4-Cl-Ph 884 2,4-Cl2-Ph 885 4-Br-Ph 886 2-CF3-Ph 887 3-CF3-Ph 888 4-CF3-Ph 889 Ph 890 2-F-Ph 891 3-F-Ph 892 4-F-Ph 893 2,4-F2-Ph 894 2-Cl-Ph 895 3-Cl-Ph 896 4-Cl-Ph 897 2,4-Cl2-Ph 898 4-Br-Ph 899 2-CFj-Ph 2-CH30-Ph 2-CH30-Ph 2-CH30-Ph 2-CH30-Ph 2-CH30-Ph 2-CH^0-Ph 2-CH30-Ph 2-CH30-Ph 2-CH30-Ph 2-CH30-Ph 4-CF30-Ph 4-CF30-Ph 4-CF30-Ph 4—CFjO-Ph 4—CFjO-Ph 4-CF30-Ph 4-CFjO-Ph 4-CFjO-Ph 4-CF30-Ph 4-CFjO-Ph 4-CF30-Ph 0 H H H H H 56-70 138-139.5 (•H C 0 ) v 2 2 4 0 H H H H H O H H H H H 0 H H H H H 0 H H H H H 0 H H H H H 0 H H H H H 0 H H H H H 0 H H H H H 0 H H H H H 0 H H H H H 0 H H H H H O H H H H H 0 H H H H H 0 H H H H H 0 H H H H H 0 H H H H H 0 H H H H H 0 H H H H H 0 H H H H H 0 H H H H H 62 - r.>:"ry.r: 234 84 1 63 Table 1 (Continued) n n, Ex.
Ko. 900 901 902 903 904 905 906 907 908 909 910 911 912 913 914 915 916 917 918 919 920 921 3-CF3-Ph 4-CF3-Ph 2-F-Ph 3-F-Ph 2,4-F2-Ph 3-Cl-Ph 2.4-Cl2-Ph 4-Br-Ph 2-CF3-Ph 3-CF3-Ph 4-CF3-Ph Ph 2-F-Ph 3-F-Ph 4-F-Ph 2,4-F2-Ph 2-Cl-Ph 3-Cl-Ph 4-Cl-Ph 2,4-Cl2-Ph 4-Br-Ph 2-CF3-Ph B n R R1 R2 R3 R* M.P.*C 4-CF30-Ph 0 H H H H H 4-CF30-Ph 0 H H H H H 3,4-Cl2-Ph 0 H H H H H 3,4-Cl2-Ph 0 H H H H H 3,4-Cl2-Ph 0 H H H H H 3,4-Cl2-Ph 0 H H H H H 110-111 3,4-Cl2-Ph 0 H H H H H 3,4-Cl2-Ph 0 H H H H H 3,4-Cl2-Ph 0 H H H H H 3.4-Cl2-Ph 0 H H H H H 3.4-Cl2-Ph 0 H H H H H 2.5-F2-Ph 0 H H H H H 2,5-F2-Ph 0 H H H H H 2,5-F2-Ph 0 H H H H H 2,5-F2-Ph 0 H H H H H 2,5-F2-Ph 0 H H H H H 2,5-F2-Ph 0 H H H H H 2,5-F2-Ph 0 H H H H H 2,5-F2-Ph 0 H H H H H 2,5-F2-Ph 0 H H H H H 2,5-F2-Ph 0 H H H H H 2,5-F2-Ph O H H H H H 63 ^rr'r;wX?idtor<w-' 1 1 i < O o w 234 84 1 64 Table 1 (Continued) Ex.
Ko.
A B n H R is 2 _ R is! 922 3-CF3-Ph 2,5-F2-Ph 0 H H H H H 923 4-CF3-Ph 2,5-F2-Ph 0 H H H H H 924 Ph 2,5-Cl2-Ph 0 H H H H H 925 2-F-Ph 2,5-Cl2-Ph 0 H H H H H 926 3-F-Ph 2,5-Cl2-Ph 0 H H H H K 927 4-F-Ph 2,5-Cl2-Ph 0 H H H H H 928 2,4-F2-Ph 2,5-Cl2-Ph 0 H H H H H 929 2-Cl-Ph 2,5-Cl2-Ph 0 H H H H H 930 3-Cl-Ph 2,5-Cl2-Ph 0 H H H H H 931 4-Cl-Ph 2,5-Cl2-Ph 0 H H H H H 932 2,4-Cl2-Ph 2,5-Cl2-Ph 0 H H H H H 933 4-Br-Ph 2,5-Cl2-Ph 0 H H H H H 934 2-CF3-Ph 2,5-Cl2-Ph 0 H H H H H 935 3-CF3-Ph 2,5-Cl2-Ph 0 H H H H H 936 4-CF3-Ph 2,5-Cl2-Ph 0 H H H H H 937 Ph 2,4,6-F3-Ph 0 H H H H H 938 2-F-Ph 2,4,6-F3-Ph 0 H H H H H 939 3-F-Ph 2,4,6-F3-Ph 0 H H H H H 940 4-F-Ph 2,4,6-F3-Ph 0 H H H H H 941 2,4-F2-Ph 2,4,6-F3-Ph 0 H H H H H 942 2-Cl-Ph 2.4,6-F3-Ph 0 H H H H H 943 3-Cl-Ph 2,4,6-F3-Ph 0 H H H H H 944 4-Cl-Ph 2,4,6-F3-Ph 0 H H H H H 64 i 2 3 4 8 4 1 65 Table 1 (Continued) I O Ex.
Wo. 945 946 947 948 949 950 951 952 953 954 955 956 957 958 959 960 961 962 2,4-Cl2-Ph 4-Br-Ph 2-CF3-Ph 3-CFg-Ph 4-CF3-Ph Ph 2-F-Ph 3-F-Ph 4-F-Ph 2.4-F2-Ph 2-Cl-Ph 3-Cl-Ph 4-Cl-Ph 2,4-Cl2-Ph 4-Br-Ph 2-CF3-Ph 3-CF3-Ph 4-CF3-Ph 963 964 965 966 967 2-F-Ph 3-F-Ph 2.4-F2-Ph 3-Cl-Ph 2,4-Cl2-Ph 968 4-Br-Ph 2.4,6-F3-Ph 2.4,6-F3-Ph 2.4,6-F3-Ph 2.4,6-F3-Ph 2,4,6-F3-Ph 2,4,5-F3-Ph 2,4,5-F3-Ph 2,4,5-F3-Ph 2,4,5-F3-Ph 2,4,5-F3-Ph 2,4,5-F3-Ph 2,4,5-F3-Ph 2,4,5-F3-Ph 2,4,5-F3-Ph 2,4,5-F3-Ph 2,4,5-F3-Ph 2,4,5-F3-Ph 2,4,5-F3-Ph 2-Cl-4-F-Ph 2-Cl-4-F-Ph 2-Cl-4-F-Ph 2-Cl-4-F-Ph 2-Cl-4-F-Ph 2-Cl-4-F-Ph 12 3 4 n R R R R R M.P. #C 0 h h h h h 0 h h h h h 0 h h h h h 0 h h h h h o h h h h h 0 h h h h h 0 h h h h h 0 h h h h h 0 h h h h h o h h h h h 0 h h h h h o h h h h h o h h h h h 0 h h h h h o h h h h h 0 h h h h h o h h h h h o h h h h h o h h h h h 0 h h h h h o h h h h h o h h h h h o h h h h h 0 h h h h h 65 © 66 Table 1 (Continued) .! . 2 34 8 4 1 o Ex. Ho.
A B n R R 1 R 2 r»3 4 R R 969 2-CF3-Ph 2-Cl-4-F-Ph 0 H H H H H 970 3-CF3-Ph 2-Cl-4-F-Ph 0 H H H H H 971 4-CF3-Ph 2-Cl-4-F-Ph 0 H H H H H 972 Ph 4-F-l-naphthyl 0 H H H H H 973 2-F-Ph 1-naphthyl 0 H H K H H 974 3-F-Ph 1-naphthyl 0 H H H H H 975 4-F-Ph 1-naphthyl 0 H H H H H 976 2,4-F2-Ph 1-naphthyl 0 H H H H H 977 2-Cl-Ph 1-naphthyl 0 H H H H H 978 3-Cl-Ph 1-naphthyl 0 H H H H H 979 4-Cl-Ph 1-naphthyl 0 H H H H H 980 2,4-Cl2-Ph 1-naphthyl 0 H H H H H 981 4-Br-Ph 1-naphthyl 0 H H H H H 982 2-CF3-Ph 1-naphthyl 0 H H H H H 983 3-CF3-Ph 1-naphthyl 0 H H H H H 984 4-CF3-Ph 1-naphthyl 0 H H H H H 985 Ph 6-Cl-2-naphthyl 0 H H H H H 986 2-F-Ph 2-naphthyl 0 H H H H H 987 3-F-Ph 2-naphthyl 0 H H H H H 988 4-F-Ph 2-naphthyl 0 H H H H H 989 2,4-F2-Ph 2-naphthyl 0 H H H H H 990 2-Cl-Ph 2-naphthyl 0 H H H H H 991 3-Cl-Ph 2-naphthyl 0 H H H H H 992 4-Cl-Ph 2-naphthyl 0 H H H H H 993 2,4,-Cl2-Ph 2-naphthyl 0 H H H H H 994 4-Br-Ph 2-naphthyl 0 H H H H H M.P.*C 66 y •■(•m. •• .-lit »-s s-.v £3 4 84 1 67 Table 1 (Continued) EX. Ho.
B o 995 2-CF3-Ph 996 3-CF3-Ph 997 4-CF3-Ph 999 Ph 999 2-F-Ph 1000 3-F-Ph 1001 4-F-Ph 1002 2,4-F2-Ph 1003 2-Cl-Ph 1004 3-Cl-Ph 1005 4-Cl-Ph 1006 2,4-Cl2-Ph 1007 4-Br-Ph 1008 2-CF3-Ph 1009 3-CF3-Ph 1010 4-CF3-Ph 1011 Ph 1012 2-F-Ph 1013 3-F-Ph 1014 4-F-Ph 1015 2,4-F2-Ph 1016 2-Cl-Ph 2-naphthyl 2-naphthyl 2-naphthyl PhCH2- PhCH„ PhCH2- PhCH2- PhCH2- PhCH2- PhCH2- PhCH2- PhCH2- PhCH2- PhCH2- PhCH2- PhCH2- PhCH(CH3) PhCH(CH3) PhCH(CH3) PhCH(CH3) PhCH(CH3) PhCH(CH3) 2 1 l! l! E! H.P.'C 0 H H H H H 0 H H H H H 0 H H H H H 0 H H H H H 0 H H H H H 0 H H H H H 0 H H H H H 0 H H H H H 0 H H H H H 0 H H H H H 0 H H H H H 0 H H H H H 0 H H H H H 0 H H H H H 0 H H H H H 0 H H H H H 0 H H H H H 0 H H H H H 0 H H H H H 0 H H H H H 0 H H H H H 0 H H H H H 67 **#» ko 4 8 4 1 V-r'' 68 Table 1 (Continued) Ex.
No. A B n R R Ik ?R is! 1017 3-Cl-Ph PhCH(CH3) 0 H H H H H 1018 4-Cl-Ph PhCH(CH3) 0 H H H H H 1019 2,4-Cl2-Ph PhCH(CH3) 0 H H H H H 1020 4-Br-Ph PhCH(CH3) 0 H H H H H 1021 2-CF„-Ph 3 PhCH(CH3) 0 H H H H H 1022 3-CF^-Ph PhCH(CH3) 0 H H H H H 1023 4-CF -Ph 3 PhCH<CH3) 0 H H H H H 1024 Ph PhC(CH3)2- 0 H H H H H 1025 2-F-Ph PhC(CH3)2- 0 H H H H H 1026 3-F-Ph PhC(CH3)2- 0 H H H H H 1027 4-F-Ph PhC(CH3)2- 0 H H H H H 1028 2,4-F2-Ph PhC(CH3)2- 0 H H H H H 1029 2-Cl-Ph PhC(CH3)2- 0 H H H H H 1030 3-Cl-PH PhC(CH3)2- 0 H H H H H 1031 4-Cl-Ph PhC(CH3)2- 0 H H H H H 1032 2,4-Cl2-Ph PhC(CH3)2- 0 H H H H H 1033 4-Br-Ph PhC(CH3)2- 0 H H H H K 1034 2-CF3-Ph PhC(CH3)2- 0 H H H H H 1035 3-CF3-Ph PhC(CH3)2- 0 H H H H H 1036 4-CF3-Ph PhC(CH3)2- 0 H H H H H 1037 Ph 4—Cl-PhC(CH3)2- O H H H H H 1038 2-F-Ph 4-Cl-PhC(CH ) - O H H H H H 68 '""•'®K4aa;-' —v,——'.-.v. - 23 4 8 4 1 69 Table 1 (Continued) Ex.
Ko. A B G O 1039 3-F-Ph 1040 4-F-Ph 1041 2,4-F2-Ph 1042 2-Cl-Ph 1043 3-Cl-Ph 1044 4-Cl-Ph 1045 2,4-Cl2-Ph 1046 4-Br-Ph 104 7 2-CF -Ph 3 4-Cl-PhC(CH3)2-4-Cl-PhC(CH ) - J 6 4-Cl-PhC(CH3)2-4-Cl-PhC(CH3)2-4-Cl-PhC(CH3)2-4-Cl-PhC(CH3)2-4-Cl-PhC(CH3)2-4-Cl-PhC(CH3)2-4-Cl-PhC(CH3) — n R R1 R2 R3 R4 M.P.'C 0 H H H H H 0 H H H H H 0 H H H H H 0 H H H H H 0 H H H H H O H H H H H 0 H H H H H 0 H H H H H O H H H H H 1048 3-CF3-Ph 4-Cl-PhC(CH3)2- 0 H H H H H 1049 4-CF3-Ph 4-Cl-PhC(CH3)2- 0 H H H H H 1050 Ph 2-thienyl 0 H H H H H 1051 2-F-Ph 2-thienyl 0 H H H H H 1052 3-F-Ph 2-thienyl 0 H H H H K 1053 4-F-Ph 2-thienyl 0 H H H H H 1054 2,4-F2-Ph 2-thienyl 0 H H H H H 1055 2-Cl-Ph 2-thienyl 0 H H H H H 1056 3-Cl-Ph 2-thienyl 0 H H H H H 1057 4-Cl-Ph 2-thienyl 0 H H H H H 1058 2,4-Cl2-Ph 2-thienyl 0 H H H H H 1059 4-Br-Ph 2-thienyl 0 H H H H H 1060 2-CF3-Ph 2-thienyl 0 H H H K H 1061 3-CF3-Ph 2-thienyl 0 H H H H H 1062 4-CF3-Ph 2-thienyl 0 H H H H H 69 i. 70 Table 1 (Continued) 23 4 8 4 1 Ex.
Ho. o 1063 Ph 1064 2-F-Ph 1065 3-F-Ph 1066 4-F-Ph 106 7 2,4-F2-Ph 1068 2-Cl-Ph 1069 3-Cl-Ph 1070 4-Cl-Ph 1071 2,4-Cl2-Ph B 3-thienyl 3-thienyl 3-thienyl 3-thienyl 3-thienyl 3-thienyl 3-thienyl 3-thienyl 3-thienyl 12 3 4 n R R R R R M.P.'C 0 H H H H H 0 H H H H H 0 H H H H H 0 H H H H H 0 H H H H H 0 H H H H H 0 H H H H H 0 H H H H H 0 H H H H H 1072 4-Br-Ph 3-thienyl 0 H H H H H 1073 2—CF^-Ph 3-thienyl 0 H H H H H 1074 3-CF3-Ph 3-thienyl 0 H H H H H 1075 4—CF3-Ph 3-thienyl 0 H H H H H 1076 2-F-Ph 2-Cl-3-thienyl 0 H H K H H 1077 3-F-Ph 2-Cl-3-thienyl 0 H H H H H 1078 2,4-F2-Ph 2-Cl-3-thienyl 0 H H H H H 1079 3-Cl-Ph 2-Cl-3-thienyl 0 H H H H H 1080 2,4-Cl2-Ph 2-Cl-3-thienyl 0 H H H H H 1081 4-Br-Ph 2-Cl-3-thienyl 0 H H H H H 1082 2-CF3-Ph 2-Cl-3-thienyl 0 H H H H H 1083 3-CF3-Ph 2-Cl-3-thienyl 0 H H H H H 1084 4-CF3-Ph 2-Cl-3-thienyl 0 H H H H H 1085 2-F-Ph -Cl-2-thienyl 0 H H H H H 1086 3-F-Ph -Cl-2-thienyl 0 H H H H H 1087 2.4-F2-Ph -Cl-2-thienyl 0 H H H H H 70 234 84 1 71 Table 1 (Continued) * Ex.
No. 12 3 4 H I L B_ L L M.P.'C 1088 3-Cl-Ph -Cl-2-thienyl 0 H H H H H 1089 2,4-Cl2-Ph -C1-2-thienyl 0 H H H H H 1090 4-Br-Ph -Cl-2-thienyl 0 H H H H H 1091 2-CF3-Ph -Cl-2-thienyl 0 H H H H H 1092 3-CF -Ph 3 -Cl-2-thienyl 0 H H H H H 1093 4-CF3-Ph -Cl-2-thienyl 0 H H H H H 1094 Ph 2,5-Cl2-3-thienyl 0 H H H H H 1095 2-F-Ph 2,5-Cl2-3-thienyl 0 H H H H H 1096 3-F-Ph 2,5-Cl2-3—thienyl 0 H H H H H 1097 4-F-Ph 2,5-Cl2-3-thienyl 0 H H H H H 1098 2,4-F2-Ph 2,5-Cl2~3-thienyl 0 H H H H H 1099 2-Cl-Ph 2,5-Cl2~3-thienyl 0 H H H H H 1100 3-Cl-Ph 2,5-Cl2-3-thienyl 0 H H H H H 1101 4-Cl-Ph 2,5-Cl2-3—thienyl 0 H H H H H 1102 2,4-Cl2-Ph 2,5-Cl2~3-thienyl 0 H H H H H 1103 4-Br-Ph 2,5-Cl2~3-thienyl 0 H H H H H 1104 2-CF3-Ph 2,5-Cl2-3-thieny1 0 H H H H H 1105 3-CF3-Ph 2,5-Cl2~3-thienyl 0 H H H H H 1106 4-CF3-Ph 2,5-Cl2-3-thienyl 0 H H H H H 1107 Ph -bromo-2-thienyl 0 H H H H H 1108 2-F-Ph -bromo-2-thienyl 0 H H H H H 1109 3-F-Ph -bromo-2-thienyl 0 H H H H H 1110 4-F-Ph -bromo-2-thienyl 0 H H H H H 1111 2,4-F2-Ph -bromo-2-thienyl 0 H H H H H 71 _'. J 234 84 1 72 Table 1 (Continued) k -» "8 1 *2 18 c- 1 i i -•i i 3 o Ex.
No. 1112 2-Cl-Ph 1113 3-Cl-Ph 1114 4-Cl-Ph 1115 2,4-Cl -Ph 2 1116 4-Br-Ph 1117 2-CF3-Ph 1118 3-CF3-Ph 1119 4-CF3-Ph 1120 Ph 1121 2-F-Ph 1122 3-F-Ph 1123 2,4-F2-Ph 1124 2-Cl-Ph 1125 3-Cl-Ph 1126 4-Cl-Ph 1127 2,4-Cl2-Ph 1128 4-Br-Ph 1129 2-CF3-Ph 1130 3-CFj-Ph 1131 4-CF3-Ph 1132 Ph 1133 2-F-Ph 30 1134 3-F-Ph 1135 4-F-Ph 1136 2,4-F2-Ph 1137 2-Cl-Ph B -bromo-2-thienyl 5-bromo-2-thienyl 5-bromo-2-thienyl 5-bromo-2-thienyl -bromo-2-thienyl 5-bromo-2-thienyl -bromo-2-thienyl -bromo-2-thienyl 2-pyridyl 2-pyridyl 2-pyridyl 2-pyridyl 2-pyridyl 2-pyridyl 2-pyridyl 2-pyridyl 2-pyridyl 2-pyridyl 2-pyridyl 2-pyridyl 3-pyridyl 3-pyridyl 3-pyridyl 3-pyridyl 3-pyridyl 3-pyridyl 12 3 4 n R R R R R M.P.'C 0 H H H H H 0 H H H H H 0 H H H K H 0 H H H H H 0 H H H H H 0 H H H H H 0 H H H H H 0 H H H H H 0 H H H H H 0 H H H H H 0 H H H H H 0 H H H H H 0 H H H H H O H H H H H 0 H H H H H 0 H H H H H O H H H H H O H H H H H 0 H H H H H 0 H H H H H O H H H H H 0 H H H H H O H H H H H O H H H H H O H H H H H O H H H H H 72 *s U j V-;^v *<tteii' tf>'V v/.-"-'' V'--"•' 234 84 1 73 Table 1 (Continued) o EX.
No. A B n ssl !■ „2 _3 R R It 1138 3-Cl-Ph 3-pyridyl 0 H H H H H 1139 4-Cl-Ph 3-pyridyl 0 H H H H H 1140 2,4-Cl2-Ph 3-pyridyl 0 H H H H H 1141 4-Br-Ph 3-pyridyl 0 H H H H H 1142 2-CF^-Ph 3-pyridyl 0 H H H H H 1143 3-CF3-Ph 3-pyridyl 0 H H H H H 1144 4-CF3-Ph 3-pyridyl 0 H H H H H 1145 Ph 4-pyridyl 0 H H H H H 1146 2-F-Ph 4-pyridyl 0 H H H H H 1147 3-F-Ph 4-pyridyl 0 H H H H H 1148 2,4-F2-Ph 4-pyridyl 0 H H H H H 1149 2-Cl-Ph 4-pyridyl 0 H H H H H 1150 3-Cl-Ph 4-pyridyl 0 H H H H H 1151 4-Cl-Ph 4-pyridyl 0 H H H H H 1152 2,4-Cl2-Ph 4-pyridyl 0 H H H H H 1153 4-Br-Ph 4-pyridyl 0 H H H H H 1154 2-CF3-Ph 4-pyridyl 0 H H H H H 1155 3-CF3-Ph 4-pyridyl 0 H H H H H 1156 4-CF3-Ph 4-pyridyl 0 H H H H H 1157 Ph 2-Cl-3-pyridyl 0 H H H H H 1158 2-F-Ph 2-Cl-3-pyridyl 0 H H H H H 1159 3-F-Ph 2-Cl-3-pyridyl 0 H H H H H 1160 4-F-Ph 2-Cl-3-pyridyl 0 H H H H H 1161 2,4-F2-Ph 2-Cl-3-pyridyl 0 H H H H H 1162 2-Cl-Ph 2-Cl-3-pyridyl 0 H H H H H 1163 3-Cl-Ph 2-Cl-3-pyridyl 0 H H H H H 1164 4-Cl-Ph 2-Cl-3-pyridyl 0 H H K H H 1165 2,4-Cl2-Ph 2-Cl-3-pyridyl 0 H H H H H M.P.*C 73 1 234 84 1 7 4 Table 1 (Continued) Ex.
No.
B 12 3 4 BlLLLL M.P.*C 1166 4-Br-Ph 2-Cl-3-pyridyl 0 H H H H H 1167 2-CF3-Ph 2-Cl-3-pyridyl 0 H H H H H 1168 3-CF^-Ph 2-Cl-3-pyridyl 0 H H H H H 1169 4-CF3-Ph 2-Cl-3-pyridyl 0 H H H H H 1170 Ph 3-Cl-2-pyridyl 0 H H H H H 1171 2-F-Ph 3-Cl-2-pyridyl 0 H H H H H 1172 3-F-Ph 3-Cl-2-pyridyl 0 H H H H H 1173 4-F-Ph 3-Cl-2-pyridyl 0 H H H H H 1174 2,4-F2-Ph 3-Cl-2-pyridyl 0 H H H H H 1175 2-Cl-Ph 3-Cl-2-pyridyl 0 H H H H H 1176 3-Cl-Ph 3-Cl-2-pyridyl 0 H H H K H 1177 4-Cl-Ph 3-Cl-2-pyridyl 0 H H H H H 1178 2,4-Cl2-Ph 3-Cl-2-pyridyl 0 H H H H H 1179 4-Br-Ph 3-Cl-2-pyridyl 0 H H H H H 1180 2-CF3-Ph 3-Cl-2-pyridyl 0 H H H H H 1181 3-CF3-Ph 3-Cl-2-pyridyl 0 H H H H H 1182 4-CF3-Ph 3-Cl-2-pyridyl 0 H H H H H 1183 2-F-Ph -Cl-2-pyridyl 0 H H K H H 1184 3-F-Ph -Cl-2-pyridyl 0 H H H H H 1185 2,4-F -Ph -Cl-2-pyridyl 0 H H H H H 1186 3-Cl-Ph S-Cl-2-pyridyl 0 H H H H H 1187 2,4-Cl2-Ph -Cl-2-pyridyl 0 H H H H H 1188 4-Br-Ph -Cl-2-pyridyl 0 H H H H H 1189 2-CF3-Ph -Cl-2-pyridyl 0 H H H H H 1190 3-CF3-Ph -Cl-2-pyridyl 0 H H H H H 1191 4-CF3-Ph -Cl-2-pyridyl 0 H H H H H 1192 Ph 6-Cl-3-pyridyl 0 H H H H H 74 t11 'f' rrr 234 84 1 75 Table 1 (Continued) n Ex.
No. n R R1 R2 R3 R4 M.P.'C 1193 2-F-Ph 6-Cl-3-pyridyl 0 H H H H H 1194 3-F-Ph 6-Cl-3-pyridyl 0 H H H H H 1195 4-F-Ph 6-Cl-3-pyridyl 0 H H H H H 1196 2,4-F^-Ph 6-Cl-3-pyridyl 0 H H H H H 1197 2-Cl-Ph 6-Cl-3-pyridyl 0 H H H H H 1198 3-Cl-Ph 6-Cl-3-pyridyl 0 H H H H H 1199 4-Cl-Ph 6-Cl-3-pyridyl 0 H H H H K 1200 2,4-Cl2-Ph 6-Cl-3-pyridyl 0 H H H H H 1201 4-Br-Ph 6-Cl-3-pyridyl 0 H H H H H 1202 2-CF^-Ph 6-Cl-3-pyridyl 0 H H H H H 1203 3-CF3-Ph 6-Cl-3-pyridyl O H H H H H 1204 4-CF3-Ph 6-Cl-3-pyridyl 0 H H H H H 1205 2-thienyl 2-thienyl 0 H H H H H 1206 3-thienyl 2-thienyl 0 H H H H H 1207 2-Cl-3-thienyl 2-thienyl 0 H H H H H 1208 5-Cl-2-thienyl 2-thienyl 0 H H H H H 1209 2,5-Cl2-3-thienyl 2-thienyl 0 H H H H H 1210 2-thienyl 3-thienyl 0 H H H H H 1211 3-thienyl 3-thienyl 0 H H H H H 1212 2-Cl-3-thienyl 3-thienyl 0 H H H H H 1213 5-Cl-2-thienyl 3-thienyl 0 H H H H H 1214 2,5-Cl2-3-thienyl 3-thienyl 0 H H H H H 1215 2-thienyl 2-C1-3-thienyl 0 H H H H H 1216 3-thienyl 2-Cl-3-thienyl 0 H H H H H 1217 2-Cl-3-thienyl 2-Cl-3-thienyl 0 H H H H H 1218 5-C1-2-thienyl 2-C1-3-thienyl 0 H H H H H 1219 2,5-Cl2-3-thienyl 2-Cl-3-thienyl 0 H H H H H 1220 2-thienyl -C1-3-thienyl 0 H H H H H 75 /jWWMlUuiitlU -J ^"raw- 76 Table 1 (Continued) 234 8 Ex.
R H.P.'C w No.
A B n R R1 R' !B III M 1221 3-thienyl -Cl-3-thienyl 0 H H H H H 1222 2-Cl-3-thienyl -Cl-3-thienyl 0 H H H H H 1223 -C1-2-thienyl -Cl-3-thienyl 0 H H H H H 1224 2,5-Cl2-3- -thienyl -Cl-3-thienyl 0 H H H H H 1225 2-thienyl 2,5-Cl2-3-thienyl 0 H H H H H 1226 3-thienyl 2,5-Cl2-3-thienyl 0 H H H H H 1227 2-Cl-3-thienyl 2,5-Cl2-3-thienyl 0 H H H H H 1228 -Cl-2-thienyl 2,5-Cl2-3-thienyl 0 H H H H H 1229 2.5-Cl2-3- thienyl 2,5-Cl2-3-thienyl 0 H H H H H 1230 thienyl -F-2-thienyl 0 H H H H H 1231 3-pyridyl -Cl-2-pyridyl 0 H H H H H 1232 -Cl-2-pyridyl -Cl-2-pyridyl 0 H H H H H 1233 4-pyridyl -Cl-2-pyridyl 0 H H H H H 1234 2-Cl-3-pyridyl -Cl-2-pyridyl 0 H H H H H 1235 2-pyridyl -Cl-2-pyridyl 0 H H H H H 1236 4-F-Ph 4-F-Ph 0 H H H °2 :H5 H 1237 4-F-Ph 4-F-Ph 0 H H H n- C3H7 H 1238 4-F-Ph 4-F-Ph 0 H H H n- C4H9 H 1239 4-F-Ph 4-F-Ph 0 H H H i- C3H7 H 1240 4-F-Ph 4-F-Ph 0 K H H s_- C4H9 H 1241 2-Cl-Ph 4-Cl-Ph 0 H H H C2 H5 H 1242 2-Cl-Ph 4-Cl-Ph 0 H H H n- C3H7 H 1243 2-Cl-Ph 4-Cl-Ph 0 H H H n- °4H9 H 1244 2-Cl-Ph 4-Cl-Ph 0 H H H i- C3H7 H 1245 2-Cl-Ph 4-Cl-Ph 0 H H H £— C4H9 H 1246 4-Cl-Ph 2.4-Cl2-Ph 0 H H H C2 H5 H 76 <d 77 Table 1 (Continued) ^X' 12 3 4 Ho. A B nRR_ R_f R_ H.P.'C 124 7 4-Cl-Ph 2,4-Cl2-Ph 0 H H H n-^Hy H 1248 4-Cl-Ph 2,4-Cl2-Ph 0 H H H n-C^Hg H 1249 4-Cl-Ph 2,4-Cl2-Ph 0 H H H H (<}; 1250 4-Cl-Ph 2,4-Cl -Ph 0 H H H s-C H H V_> 2 — 4 9 1251 Ph 4-F-Ph 0 H H H C,Hr K 2 5 1252 Ph 4-F-Ph 0 H H H H 1253 Ph 4-F-Ph 0 H H H n-CAH„ H - 4 9 1254 Ph 4-F-Ph 0 H H H i-^Hy H 1255 Ph 4-F-Ph 0 H H H s-C^ H - 4 9 1256 4-F-Ph 4-F-Ph 0 H H H CH3 H 1257 4-F-Ph 4-F-Ph 0 H H H CH3 CH3 1258 4-F-Ph 4-F-Ph 0 H H H F H 166-167 1259 4-F-Ph 4-F-Ph 0 H H H F CH3 1260 4-F-Ph 4-F-Ph O H H H F F 145-147 1261 4-Cl-Ph 2,4-Cl2-Ph O H H H CHg H 1262 4-Cl-Ph 2,4-Cl2-Ph O H H H CH3 CH3 1263 4-Cl-Ph 2,4-Cl2-Ph 0 H H H F H 1264 4-Cl-Ph 2,4-Cl2-Ph 0 H H H F CH3 1265 4-Cl-Ph 2,4-Cl2-Ph O H H H F F 1266 2-Cl-Ph 4-Cl-Ph 0 H H H CH3 H 1267 2-Cl-Ph 4-Cl-Ph 0 H H H CH3 CH3 1268 2-Cl-Ph 4-Cl-Ph O H H H F H 1269 2-Cl-Ph 4-Cl-Ph O H H H F CH3 1270 2-Cl-Ph 4-Cl-Ph 0 H H H F F o 77 ggSBSSSfcUfi-., W* V^Xr" V /"■*> 23 4 8 4 1 78 Table 1 (Continued) Ex. Mo.
A B n R al s! R! £ 1271 Ph 4-F-Ph 0 H H H CH3 H 1272 Ph 4-F-Ph 0 H H H CH3 CH3 1273 Ph 4-F-Ph 0 H H H F H 1274 Ph 4-F-Ph 0 H H H F CH3 1275 Ph 4-F-Ph 0 H H H F F a NMR: : (CDCl ) 6 4 .70 (q.
J*14Hz, 2H); 4.90 (s.
IH); .40 (s . IH); 5 .55 (s.
IH); 6.8- (m. 4H); 7.2-7.4 (m. 4H) . 7. 8 (bs, 2H). b NMR: (CDC13) 6 4.8 (q. 2H), .2 (s, 1H), .3 (s,lH), 5.6 (s, IH), 6.9 -7.6 (m, 8H), (s.
IH), 8.1 (s, IH) M.P.'C c NMR: (CDCl3) 6 4.70 (q, J-13HZ, 2H); 4.85 (s, IH); 5.35 (s, IH); 5.55 <s, IH); 6.85-7.4 (m, 8H); 7.7 (s, H); 7.9 (s, IH). d NMR: (CDC13) 6 4.60 (q, J«12Hz, 2H); 5.0 25 (s, IH); 5.40 (s, IH); 5.55 (s, IH); 6.8 (1/2 of ABq, J-lOHz, 2H); 7.00 (m, 2H); 7.3 (1/2 of ABq, J-lOHz, 2H); 7.45 (m, 2H); 7.80 (s, IH); 7.85 (s, IH). e NMR: (CDC13) 6 4.6, 4.8 (ABq, J=14Hz, 2H); 4.9 (br s, 3H); 5.3 (s, IH); 5.6 (s, IH); 6.8 (d, IH); 7.0 (m, 3H); 7.4 (m, 3H); 7.8 (s, IH); 7.9 (s, IH). 78 79 f NMR: (CDC13) 6 1.3 (s, 9H), 4.7 (q, 2H), 4.6 (s, IH). 5.0 (s, IH), 5.4 (s, IH), 6.8-7.4 (9H), 7.8 (s, IH).
O 5 g NMR: (CDC13> 6 4.7, 4.8 (ABq, J*12Hz, 2H); 6.7-7.5 (m, 14H); 7.9 (s, IH); 8.0 (s, IH). h NMR: (CDC13) 6 3.45 (s, 3H); 4.75 (ABq, J-18HZ, 14Hz, 2H); 4.6 (m, 2H); 6.8-7.0 (m, 4H) O 10 7.05-7.25 (m, 4H); 8.0 (s, IH); 8.25 (s, IH). i NMR: (CDC13) 6 4.0 (dd, 14, 4Hz, IH); 4.3 (dd, 14, 4Hz, IH); 4.6 (d, 13Hz, IH); 4.9 (d, 13Hz, IH); 5.1 (d, IH); 5.3 (d, IH); 5.55 (s, 15 IH); 5.60 (s, IH); 5.85 (m, IH); 6.8-7.0 (m, 4H); 7.05-7.2 (m, 4H); 8.05 (s, IH); 8.25 (s, IH). j NMR: (CDC13) 6 1.90 (s, 3H); 4.80 (1/2 of 20 ABq, J=14Hz, IH); 5.65 (1/2 of ABq, J»14Hz, IH) .55 (s, IH); 5.60 (s, IH); 6.75-7.0 (m, 4H); 7.0-7.2 (t, 2H); 7.25-7.4 (m, 2H); 7.35 (s, IH) 7.85 (s, IH). k NMR: (CDCl3) 6 4.03, 4.11 (ABq, J=llHz, 2H); 4.25 (s, IH, OH); 4.39 (s, IH, OH), 4.54, 4.81 (ABq, J=14Hz, 2H); 5.31, 5.33 (2 sharp s, IH each); 7.25-7.40 (m, 4H); 7.71 (s, IH); 8.03 HI (s, IH).
NMR: (CDC13) 6 2.03 (s, IH, OH); 4.0-4.2 (m, 2H); 4.57, 4.85 (ABq. J=15Hz, 2H); 5.3-5.35 (m, 2H); 5.7-5.9 (broad s, IH, OH); 7.3-7.6 (m, 4H); 7.75 (s, IH); 8.11 (s, IH). 79 - ' 234 84 1 © 80 m NMR: (CDCl3) 6 2.10 (s, 6H); 2.52, 3.03 (ABq, J»12Hz, 2H); 4.41, 4.78 (ABq, J-15 Hz, 2H); 5.19 (s, IH); 5.50 (s, IH); 6.9-7.2 (in, 2H); 7.4-7.6 (m, 2H); 7.80 (s, IH); 8.36 (s, IH).
NHR: (CDC13) 6 2.11 (s, 6H); 2.61, 3.11 (ABq, J«12Hz, 2H); 4.50, 4.90 (ABq, J«13Hz, 2H); 5.13 (s, IH); 5.50 (s, IH); 7.50 (s, 4H); 7.86 (s, IH); 8.14 (s, IH).
NHR: (CDC13) 6 2.13 (s, 3H); 2.19 (s, 3H); 2.5-3.1 (in, 2H); 4.44, 4.85 (ABq, J«14Hz, 2H); 5.0-5.5 (m, 2H); 7.3-7.8 (m, 9H); 7.97 (s, IH); 8.32 (s, IH, OH); 8.50 (s, IH).
NMR: (CDC13) 6 4.6 (d, 1/2 of ABq, IH); 4.9 (d, 1/2 of ABq, IH); 5.0 (s, IH); 5.3 (two s, 2H); 6.9-7.6 (m, 9H); 7.8 (two s, 2H). q NMR: (CDC13) 6 1.0 (t, 3H); 1.2 (s, IH); 1.6 (m, 2H); 4.2 (ABq, 2H); 5.1 (s, IH); 5.4 (s, IH); 6.9-7.1 (m, 4H); 7.9 (s, IH); 8.0 (s, IH). 80 —«««.•«&, '•-•• ^A" - ' • "*•"•' ' • - -- 234 84 1 0 81 Examples 1276 and 1276a: Preparation of the (S)-enantiomer of Example 49 The compound of Example 49 (1.5 g) and 1.5 g of 5 i-a-bromocamphor-u-sulfonic acid was dissolved in 75 ml of acetonitrile and refluxed for 2 hours. The solution was allowed to cool to ambient temperature and stand for 14 hours. Filtration of the resulting solid6 followed by recrystallization from an additional G 10 portion of acetonitrile. yielded 1.28 g of white solid, mp 216-217°; [a]25 - -104° (C - 1; DMSO).
The acetonitrile can be evaporated to yield the adduct having a (+)- rotation (Example 1276a). This 15 compound can be recrystallized from an ether/acetone mixture to yield a solid, that on treatment with aqueous NaHC03 yields material identical by NHR to that of Example 49.
The solid was suspended in 50 ml of saturated 20 NaHCC>3 solution and stirred vigorously until the evolution of gas ceased (1-2 hours). The mixture was extracted twice with 50 ml of CHC13. The organic layers were combined, washed with brine, dried over Na2S04 and the solvent removed jjn vacuo. This yielded 25 750 mg of a white solid (Example 1276) having an 'H NMR identical to that of the compound of Example 49. mp » 82-83°; [a]£5 - -62° (C - 1; CHC13).
These compounds and other compounds which were 30 resolved as described above are shown in Table 2. 81 i . > j., * v — O 82 Table 2 234841 r> EX. No. 1276 (1) 1276a 1277(2) A(CH CRR1 .
T5 » B n R R1 R2 R3 R4 M.P.°C [a]25 F-^^- 0 H H H H H 82-83 -62« ^3" F"©- 0 H H H H H 83-84 +60# F-@" F-^V 0 H H H H H 60-61 -67' ^ (HCl salt 181-184) 1277a (1).(2) FF-(^- O H H H H H 60-62 +66° * denotes chiral center (1) » substitute d-a-bromocamphor-ir-sulfonic acid (2) = use a 3 parts ether - 1 part acetone mixture as solvent.
Example 1278 Preparation of 2-(4-fluorophenyl)-3-phenyl-l-(5-mercapto-lH-1.2.4-triazol-l-yl)-3-buten-l-ol To a solution of 1.24 g (0.004 mol) of 2-(4-fluoro-pheny1)-3-pheny1-1-(1H-1.2,4-triazol-l-yl)-3-buten-2-ol in 15 mL of THF at -70° was added 5.2 mL (0.008 mol) of a 1.55 M solution of n-butyllithium in hexanes over 5 minutes. After 30 minutes. 0.13 g (0.004 raol) of sulfur was added and the reaction mixture was 82 0 v~> •< J 20 I ?; I < * 234 84 1 83 allowed to warm to room temperature over 1 h. then quenched with 8 mL of IN HCl. After pouring into saturated NH.C1, the mixture was extracted with 2 x 4 ether and the combined organic layers were washed with 5 brine, dried over Na2S04 and evaporated. The crude product was purified by flash chromatography using 2:13:85 methanol/ether/methylene chloride to give 0.85 g of the title compound, ra.p. 54-58°: NMR (CDC13) 6 4.7 (ABq. 2H). 5.0 (S. IH. OH). 5.3 (s. 10 IH. vinyl). 5.5 (s. IH. vinyl). 7.0 (ra. 4H). 7.2 (m. 3H). 7.5 (m. 2H). 7.7 (s. IH. triazole proton). 12.5 (brs. IH. SH); IR (methylene chloride) 3500-3000 (br). 1590. 1500. 1465. 1230. 1162. 1109. 825 cm"1; MS: highest m/e 341.
The compounds shown in Table 3 were prepared or can be prepared by the methods described above. 83 m: © 234 84 Table 3* X? I v Ex. No.
A B R R - I 1 2 SH 1278 Ph 4-F-Ph H H H H 1279 Ph Ph H H H H SH 1280 Ph 2-F-Ph H H H H SH 1281 Ph 2-Cl-Ph H H ' H H SH 1282 Ph 4-Cl-Ph H H H H SH 1283 Ph 2.4-F2-Ph H H H H SH 1284 Ph 2.4-Cl2-Ph H H H H SH 1285 2-F-Ph Ph H H H H SH 1286 2-F-Ph 2-F-Ph H H H H SH 1287 2-F-Ph 4-F-Ph H H H H SH 1288 2-F-Ph 2-Cl-Ph H H H H SH 1289 2-F-Ph 4-Cl-Ph H H H H SH 1290 2-F-Ph 2,4-F2-Ph H H H H SH 1291 2-F-Ph 2,4-Cl2-Ph H H H H SH 1292 3-F-Ph Ph H H H H SH 1293 3-F-Ph 2-F-Ph H H H H SH 1294 3-F-Ph 4-F-Ph H H H H SH 1295 3-F-Ph 2-Cl-Ph H H H H SH 1296 3-F-Ph 4-Cl-Ph H H H H SH 1297 3-F-Ph 2,4-F2-Ph H H H H SH 1298 3-F-Ph 2,4-Cl2-Ph H H H H SH 1299 4-F-Ph Ph H H H H SH 1300 4-F-Ph 2-F-Ph H H H H SH 1301 4-F-Ph 4-F-Ph H H H H SH 1302 4-F-Ph 2-Cl-Ph H H H H SH 54-58 144.5-148 84 23484 1 f 85 n Table 3 (continued) Ex. No.
A B R R is 2R4Q 1303 4-F-Ph 4-Cl-Ph H H H H SH 1304 4-F-Ph 2,4-F2-Ph H H H H SH 1305 4-F-Ph 2,4-Cl2-Ph H H H H SH 1306 2-Cl-Ph Ph H H H H SH 1307 2-Cl-Ph 2-F-Ph H H H H SH 1308 2-Cl-Ph 4-F-Ph H H H H SH 1309 2-Cl-Ph 2-Cl-Ph K H H H SH 1310 2-Cl-Ph 4-Cl-Ph H H H H SH 1311 2-Cl-Ph 2,4-F2-Ph H H H H SH 1312 2-Cl-Ph 2,4-Cl2-Ph H H H H SH 1313 3-Cl-Ph Ph H H H H SH 1314 3-Cl-Ph 2-F-Ph H H H H SH 1315 3-Cl-Ph 4-F-Ph H H H H SH 1316 3-Cl-Ph 2-Cl-Ph H H H H SH 1317 3-Cl-Ph 4-Cl-Ph H H H H SH 1318 3-Cl-Ph 2,4-F2-Ph H H H H SH 1319 3-Cl-Ph 2,4-Cl2-Ph H H H H SH 1320 4-Cl-Ph Ph H H H H SH 1321 4-Cl-Ph 2-F-Ph H H H H SH 1322 4-Cl-Ph 4-F-Ph K H H H SH 1323 4-Cl-Ph 2-Cl-Ph H H H H SH 1324 4-Cl-Ph 4-Cl-Ph H H H H SH 1325 4-Cl-Ph 2,4-F -Ph H H H H SH z 1326 4-Cl-Ph 2,4-Cl2-Ph H H H H SH 1327 2-CF3-Ph Ph H H H H SH 1328 2-CF3-Ph 2-F-Ph H H H H SH 1329 2-CFj-Ph 4-F-Ph H H H H SH (foam) 85 o 234841 86 Table 3 (continued) Ex.
No.
B 1330 2-CF3-Ph 1331 2-CF3-Ph 1332 2-CF3-Ph 1333 2-CF3-Ph 1334 4-CF3-Ph 1335 4-CF3-Ph 1336 4-CF3-Ph 1337 4-CF3-Ph 1338 4-CF3-Ph 1339 4-CF3-Ph 1340 4-CF3-Ph 1341 2,4-F2-Ph 1342 2,4-F2-Ph 1343 2,4-F2-Ph 1344 2,4-F2-Ph 1345 2,4-F2-Fh 1346 2,4-F2-Ph 1347 2,4-F2-Ph 1348 2,4-Cl2-Ph 1349 2.4-Cl2-Ph 1350 2,4-Cl2-Ph 1351 2,4-Cl2-Ph 1352 2,4-Cl2-Ph 2-Cl-Ph 4-Cl-Ph 2,4-F2-Ph 2,4-Cl2-Ph Ph 2-F-Ph 4-F-Ph 2-Cl-Ph 4-Cl-Ph 2,4-F2-Ph 2,4-Cl2-Ph Ph 2-F-Ph 4-F-Ph 2-Cl-Ph 4-Cl-Ph 2,4-F2-Ph 2,4-Cl2-Ph Ph 2-F-Ph 4-F-Ph 2-Cl-Ph 4-Cl-Ph Bl 5^ ii 2 H.P.-C H H H H SH H H H H SH H H H H SH H H H H SH H H H H SH H H H H SH H H H H SH H H H H SH H H H H SH H H H H SH H H H H SH H H H H SH H H H H SH H H H H SH H H H H SH H H H H SH H H H H SH H H H H SH H H H H SH H H H H SH H H H H SH H H H H SH H H H H SH 86 234 84 1 87 o Table 3 (continued) Ex. 1 *% A No.
A B R R _ R R 0 1353 2,4-Cl2 -Ph 2,4-F2-Ph H H H H SI 1354 2,4-Cl2- -Ph 2,4-Cl2-Ph H H H H St 1355 Ph Ph H H H H I 1356 Ph 2-F-Ph H H H H I 1357 Ph 4-F-Ph H H H H I 1358 Ph 2-Cl-Ph H H H H I 1359 Ph 4-Cl-Ph H H H H I 1360 Ph 2,4-F2-Ph H H H H I 1361 Ph 2,4-Cl2-Ph H H H H I 1362 2-F-Ph Ph H H H H I 1363 2-F-Ph 2-F-Ph H H H H I 1364 2-F-Ph 4-F-Ph H H H H I 1365 2-F-Ph 2-Cl-Ph H H H H I 1366 2-F-Ph 4-Cl-Ph H H K H I 1367 2-F-Ph 2,4-F2-Ph H H H H I 1368 2-F-Ph 2,4-Cl2-Ph H H H H I 1369 3-F-Ph Ph H H H H I 1370 3-F-Ph 2-F-Ph H H H H I 1371 3-F-Ph 4-F-Ph H H H H I 1372 3-F-Ph 2-Cl-Ph H H H H I 1373 3-F-Ph 4-Cl-Ph H H H H I 1374 3-F-Ph 2.4-F2-Ph H H H H I 1375 3-F-Ph 2,4-Cl_—Ph H H H H I 4. 1376 4-F-Ph Ph H H H H I 1377 4-F-Ph 2-F-Ph H H H H I 1378 4-F-Ph 4-F-Ph H H H H I 1379 4-F-Ph 2-Cl-Ph H H H H I 1380 4-F-Ph 4-Cl-Ph H H H H I 96-97.5 87 t. 88 Table 3 (continued) 23 n £i-i& Ex.
No.
R R1 R2 R4 1381 4-F-Ph 2,4-F2-Ph H H H H I 1382 4-F-Ph 2,4-Cl2-Ph H H H H I 1383 2-Cl-Ph Ph H H H H I 1384 2-Cl-Ph 2-F-Ph H H H H I 1385 2-Cl-Ph 4-F-Ph H H H H I 1386 2-Cl-Ph 2-Cl-Ph H H H H I 1387 2-Cl-Ph 4-Cl-Ph H H H H I 1388 2-Cl-Ph 2,4-F2-Ph H H H H I 1389 2-Cl-Ph 2,4-Cl2-Ph H H H H I 1390 3-Cl-Ph Ph H K H H I 1391 3-Cl-Ph 2-F-Ph H H H H I 1392 3-Cl-Ph 4-F-Ph H H H H I 1393 3-Cl-Ph 2-Cl-Ph H H H H I 1394 3-Cl-Ph 4-Cl-Ph H H H H I 1395 3-Cl-Ph 2,4-F2-Ph H H H H I 1396 3-Cl-Ph 2,4-Cl2-Ph H H H H I 1397 4-Cl-Ph Ph H H H H I 1398 4-Cl-Ph 2-F-Ph H H H H I 1399 4-Cl-Ph 4-F-Ph H H H H I 1400 4-Cl-Ph 2-Cl-Ph H H K H I 1401 4-Cl-Ph 4-Cl-Ph H H H H I 1402 4-Cl-Ph 2,4-F2-Ph H H H H I 1403 4-Cl-Ph 2,4-Cl2-Ph H H H H I 1404 2-CF3-Ph Ph H H H H I 1405 2-CF3-Ph 2-F-Ph H H H H I 1406 2-CF3-Ph 4-F-Ph H H H H I Q H.P.*C (foam) 88 234 84 1 89 Table 3 (continued) Ex.
Ho.
B n 1407 2-CF3-Ph 1408 2-CF3-Ph 1409 2-CF3-Ph 1410 2-CF3-Ph 1411 4-CF3-Ph 1412 4-CF3-Ph 1413 4-CF3-Ph 1414 4-CF3-Ph 1415 4-CF3-Ph 1416 4-CF3-Ph 1417 4-CF3-Ph 1418 2,4-F2-Ph 1419 2,4-F2-Ph 1420 2,4-F2-Ph 1421 2,4-F2-Ph 1422 2,4-F2-Ph 1423 2,4-F2-Ph 1424 2,4-F2-Ph 1425 2,4-Cl2-Ph 1426 2,4-Cl2-Ph 1427 2,4-Cl2-Ph 1428 2,4-Cl2-Ph 1429 2,4-Cl2-Ph 2-Cl-Ph 4-Cl-Ph 2,4-F2-Ph 2,4-Cl2-Ph Ph 2-F-Ph 4-F-Ph 2-Cl-Ph 4-Cl-Ph 2,4-F2-Ph 2,4-Cl2-Ph Ph 2-F-Ph 4-F-Ph 2-Cl-Ph 4-Cl-Ph 2,4-F2-Ph 2,4-Cl2-Ph Ph 2-F-Ph 4-F-Ph 2-Cl-Ph 4-Cl-Ph R R^ Q M.P.*C H H H H I H H H H I H H H H I H H H H I H H H H I H H H H I H H H H I H H H H I H H H H I H H H H I H H H H I H H H H I H H H H I H H H H I H H H H I H H H H I H H H H I H H H H I H H H H I H H H H I H H H H I H H H H I H H H H I 89 90 Table 3 (continued) 23 4 84 1 EX. Ko. o 1430 2,4-Cl2-Ph 2,4-F2-Ph 1431 2,4-Cl -Ph 2,4-Cl -Ph 1432 Ph 1433 4-F-Ph 1434 4-F-Ph 1435 Ph 1436 4-F-Ph 1437 4-F-Ph 1438 Ph 1439 4-F-Ph 1440 4-F-Ph 2,4-F2-Ph 2-F-Ph 2,4-F2-Ph 2,4-F2-Ph 2-F-Ph 2,4-F2-Ph 2,4-F2-Ph 2-F-Ph 2,4-F2-Ph « «1 «2 _4 „ R R_ R_ R_ Q H H H H I H H H H I H H H H -SS- H H H H -SS-H H H H -SS- H H H H -SSCH 3 H H H H -SSCH3 H H H H -SSCH3 0 H H H H SCNHMe 0 »• H H H H SCNHMe 0 H H H H SCNHMe H.P.'C 1441 Ph 2,4-F2-Ph H H H H SCNH-n-Bu 1442 4-F-Ph 1443 4-F-Ph 1444 Ph 1445 4-F-Ph 1446 4-F-Ph 144 7 Ph 1448 4-F-Ph 1449 4-F-Ph 2-F-Ph 2,4-F2-Ph 2,4-F2-Ph 2-F-Ph 2,4-F2-Ph 2,4-F2-Ph 2-F-Ph 2,4-F2-Ph H H H H SCNH-n-Bu O «• H H H H SCNH-n-Bu H H H H Cl H H H H Cl H H H H Cl H H H H CHO H H H H CHO H H H H CHO 90 23 4 84 / 91 Table 3 (continued) o Ex.
No. 1450 Ph B 2,4-F2-Ph 12 4 R R_ R_ R_ Q H H H H SCH2CN M.P.'C 1451 4-F-Ph 1452 4-F-Ph 1453 Ph 1454 4-F-Ph 1455 4-F-Ph 1456 Ph 1457 4-F-Ph 1458 4-F-Ph 1459 Ph 1460 4-F-Ph 1461 4-F-Ph 2-F-Ph 2,4-F2-Ph 2,4-F2-Ph 2-F-Ph 2.4-F2-Ph 2.4-F2-Ph 2-F-Ph 2,4-F2-Ph 4-F-Ph 2-F-Ph 2-F-Ph H H H H SCH2CN oil H H H H SCH2CN H H H H SCH2SCN H H H H SCH2SCN H H H H SCH2SCN H H H H SCC1..
H H H H SCC1.
H H H H SCC1. 1462 4-F-Ph 2-F-Ph H H H H S-n-Bu semi-solid H H H H F H H H H Br 0 • t H H H H SCH„ 1463 4-F-Ph 2-F-Ph 1464 4-F-Ph 2-F-Ph 1465 4-F-Ph 1466 4-F-Ph 2-F-Ph 2-F-Ph 146 7 4-F-Ph 2-F-Ph H H H H SCH fl ^ 0 O H H H H S-n-Pr f* O 0 M H H H H -S-t-Bu H H H H SCF2H H H H H SCF-CF.H 2 2 1468* 4-F-Ph 2-F-Ph H H H H SCH2CN (oil) 91 V '■ '':■ '..v '"1 I '■ ■ . 92 Table 3 (continued) 234 84 1 Ex.
Wo. A 1469* 4-F-Ph 1470 4-F-Ph 1471 4-F-Ph 1472 4-F-Ph 1 2 4 JB R R R R g 2-F-Ph H H H H SCH.CH it ^ 0 O 2-F-Ph H H H H SCH.SCH .. 2 0 0-3 2-F-Ph H H H H S-CHCW • • 0 o 2-F-Ph H H H H SCH2C02CH3 M.P.'C (oil)f 1473 4-F-Ph 14 74 4-F-Ph 1475 4-F-Ph 2-F-Ph H H H H SCNH-allyl 0 •• 2-F-Ph H H H H SCNH-i.-Pr O •« 2-F-Ph H H H H SCNHPh 1476 4-F-Ph 1477 4-F-Ph 2-F-Ph H H H H SCNH-(4-Cl-Ph) 0 •• 2-F-Ph H H H H SCNHC^Ph 1478 4-F-Ph 2-F-Ph H H H H SCNHCH2-(4-CH30-Ph) 14 79 4-F-Ph 2-F-Ph H H H H CCH, 92 * ~ ^- ? " :j,v r^; G 93 Table 3 (continued) 234 84 1 Ex. No.
A B R E! si g* 2 0 1480 4-F-Ph 2-F-Ph H H H H COH 0 1481 4-F-Ph 2-F-Ph H H H H C0CH3 0 1482 4-F-Ph 2-F-Ph H H H H CO-i-Pr 1483 4-F-Ph 2-F-Ph H H H H SCN 1484 4-F-Ph 2-F-Ph H H H H SSCH Ph 2 1485 4-F-Ph 2-F-Ph H H H H SS-allyl 1486 4-F-Ph 2-F-Ph H H H H SSPh M.P.*C *A11 compounds in this table are compounds in which E is a bond except 1468 and 1469 in which E is an oxygen atom. a NHR: (CDC13) 6 4.9 (s, 2H); 5.1 (s, IH); 5.2 (s, IH); .3 (s, IH); 6.7 (m, 2H); 6.9 (m, 2H); 7.2 (m, 2H); 7.5 (m, IH); 7.6 (s, IH); 12.2 (brs, IH). b NMR: (CDC13) 6 4.7 (ABq, 2H); 5.3 (s, 2H); 5.8 (s, IH); 6.7 (ra, 2H); 6.9 (m, 2H); 7.3 (m, 2H); 7.5 (m, IH); 7.8 (s, IH). c NMR: (CDC13) 6 3.8 (ABq, 2H); 4.7 (ABq, 2H); 5.2 (s, IH); 5.3 (two s, 2H); 6.9-7.2 (m, 4H); 7.2-7.4 (m, 3H); 7.5 (m, IH); 7.8 (s, IH). d NMR: (CDC13) 6 0.92 (t, 3H); 1.4-1.7 (m, 4H); 3.1 (t, 35 2H); 4.5 (ABq, 2H); 5.4 (two s, 2H); 5.8 (s, IH); 7.0 (ra, 4H); 7.2 (m, 3H); 7.5 (m, 2H); 7.8 (s, IH) 93 ;ISii ? * 234 84 1 I r 94 e NMR: (CDC13> 6 2.7-3.5 (in, 2H); 4.3 (s, IH); 4.4 (m, 2H); 5.2 (ra, 2H); 6.8-7.4 (m, 8H); 7.9 (m, IH). ^ f NMR: (CDC13) 6 2.7-3.4 (m, 2H); 4.2 (d, IH); 4.5 (ABq, 2H); 5.3 (ra, 2H) ; 6.8-7.4 (in, 8H) ; 7.9 (d, IH) f • - -5 4 Z-- 3 f 'i I 94 •*.-vnwr**l*>MK4;i!rt\ZmlWl«W 23 4 8 4 1 95 Example 1487 Preparation of 2.3-bis(4-fluorophenyl)-1-(IH-1.2,4-triazol-l-yl)-3.4-epoxy-2-butanol 2,3-Bis(4-fluorophenyl)-1-(1H-1.2.4-triazol-l-yl)-3-butene-2-ol (1.0 g) was dissolved in 50 ml of anhydrous benzene and stirred under nitrogen. To this solution was added .012 g of vanadium acetonyl-10 acetonate. The solution was then refluxed and tert-butyl hydroperoxide (0.44 g dissolved in 5 ml of anhydrous benzene) was added dropwise over 10 minutes. The reaction was refluxed for one additional hour and then cooled to ambient temperature. The benzene was 15 removed ijn vacuo and the residue chromatographed on silica gel (2% MeOH/CH2Cl2). This yielded a total of 650 mg of diastereomeric products in a 3:1 ratio. Further chromatography resulted in the separation of the diastereomers. The major isomer was a waxy white 20 solid. NMR (CDC13/TMS) 6 2.60 (d. J=6Hz. IH); 3.48 (d. J-6HZ. IH); 4.70 (q. J«7Hz. 2H); 5.25 (S. IH); 6.8-7.3 (ra. 8H); 7.55 (s. IH); 7.90 (s. IH).
The minor isomer was an amorphous white solid. NMR (CDC13/TMS) 6 2.55 (d. J=6H. IH); 2.75 (d. 25 J-6HZ. IH); 4.80. (q. J«7Hz); 5.0 (s. IH); 6.85 - 7.10 (m. 4H); 7.15-7.45 (m. 4H); 7.80 (s. IH); 8.05 (s. IH).
The epoxides shown in Table 4 were prepared or can be prepared by the method described in Example 1487. 95 96 Table 4 CRf^OR2 A-CCH,) -CZ—C C(H 2 n •3><V -j] // B EX. Ko.
A B n . 5 si .gf .R3 4 R H.P 1487 4-F-Ph 4-F-Ph 0 H H H H H 53- 1488 4-F-Ph 2,4-Cl2-Ph 0 H H H H H 1489 4-F-Ph 4-Cl-Ph 0 H H H H H 1490 4-F-Ph 2,4-F2-Ph 0 H H H H H 1491 4-F-Ph 4-CF3-Ph 0 H H H H H 1492 4-F-Ph 2-F-Ph 0 H H H H H 1493 4-F-Ph 2-Cl-Ph 0 H H H H H 1494 4-F-Ph H-C4F9 0 K H H H H 1495 3-F-Ph 4-F-Ph 0 H H H H H 1496 3-F-Ph 2,4-Cl2-Ph 0 H H H H H 1497 3-F-Ph 4-Cl-Ph 0 H H H H H 1498 3-F-Ph 2,4-F2-Ph 0 H H H H H 1499 3-F-Ph 4-CF^-Ph 0 H H H H H 1500 3-F-Ph 2-F-Ph 0 H H H H H 1501 3-F-Ph 2-Cl-Ph 0 H H H H H 1502 3-F-Ph G-C4F9 0 H H H H H 1503 4-Cl-Ph 4-F-Ph 0 H H H H H 1504 4-Cl-Ph 2,4-Cl2-Ph 0 H H H H H 1505 4-Cl-Ph 4-Cl-Ph 0 H H H H H 1506 4-Cl-Ph 2,4-F -Ph 0 K H H H H 96 234841 97 rr\ Ex.
No. 1507 4-Cl-Ph 1508 4-Cl-Ph 1509 4-Cl-Ph 1510 4-Cl-Ph 1511 2-Cl-Ph 1512 2-Cl-Ph 1513 2-Cl-Ph 1514 2-Cl-Ph 1515 2-Cl-Ph 1516 2-Cl-Ph 1517 2-Cl-Ph 1518 2-Cl-Ph 1519 3-Cl-Ph 1520 3-Cl-Ph 1521 3-Cl-Ph 1522 3-Cl-Ph 1523 3-Cl-Ph 1524 3-Cl-Ph 1525 3-Cl-Ph 1526 3-Cl-Ph 1527 Ph 1528 Ph 1529 Ph 1530 Ph 1531 Ph 1532 Ph Table 4 (continued) B n R R1 R2 R3 R4 M.P.'C 4-CF^-Ph 0 H H H H H 2-F-Ph 2-Cl-Ph n"C4F9 4-F-Ph 0 H H H H H 0 H H H H H 0 H H H H H 0 H H H H H 2,4-Cl2-Ph 0 H H H H H 4-Cl-Ph 0 H H H H H 2,4-F2-Ph 0 H H H H H 4-CF3-Ph 0 H H H H H 2-F-Ph 2-Cl-Ph b-c4f9 4-F-Ph 0 H H H H H 0 H H H H H 0 H H H H H 0 H H H H H 2,4-Cl2-Ph 0 H H H H H 4-Cl-Ph 0 H H H H H 2,4-F2-Ph 0 H H H H H 4-CF3-Ph 0 H H H H H 2-F-Ph 2-Cl-Ph n_C4F9 4-F-Ph 0 H H H H H 0 H H H H H 0 H H H H H 0 H H H H H 88-94 2,4-Cl2-Ph 0 H H H H H 4-Cl-Ph 0 H H H H H 2,4-F2-Ph 0 H H H H H 4-CF3-Ph 0 H H H H H 2-F-Ph 0 H H H H H 97 RSSSBse-: vi«'/ -f 234 84 1 98 Table 4 (continued) /""N Ex.
Ho. A B n R ri R! £ R4 M.P.#C 1533 Ph 2-Cl-Ph 0 H H H H H 1534 Ph S-C4F9 0 H H H H H 1535 4-CF3-Fh 4-F-Ph 0 H H H H H 1536 4-CF3-Ph 2,4-Cl2-Ph 0 H H H H H 1537 4-CF3-Ph 4-Cl-Ph 0 H H H H H 1538 4-CF3-Ph 2,4-F2-Ph 0 H H H H H 1539 4-CF3-Ph 4-CF3-Ph 0 H H H H H 1540 4-CF3-Ph 2-F-Ph 0 \ H H H H H 1541 4-CF3-Ph 2-Cl-Ph 0 H H H H H 1542 4-CF3-Ph n-C4F9 0 H H H H H 1543 4-Br-Ph 4-F-Ph 0 H H H H H 1544 4-Br-Ph 2,4-Cl2-Ph 0 H H H H H 1545 4-Br-Ph 4-Cl-Ph 0 H H H H H 1546 4-Br-Ph 2,4-F2-Ph 0 H H H H H 1547 4-Br-Ph 4-CF3-Ph 0 H H H H H 1548 4-Br-Ph 2-F-Ph 0 H H H H H 1549 4-Br-Ph 2-Cl-Ph 0 H k H H H 1550 4-Br-Ph s-c4f9 0 H h H H H 1551 2,4-Cl2-Ph 4-F-Ph 0 H H H H H 1552 2,4-Cl2-Ph 2,4-Cl2-Ph 0 H H h H H 1553 2,4-Cl2-Ph 4-Cl-Ph 0 H H H H H 1554 2,4-Cl2-Ph 2,4-F2-Ph 0 H H H H H 1555 2,4-Cl2-Ph 4-CF -Ph 3 0 H H H h H 1556 2,4-Cl2-Ph 2-F-Ph 0 H H h H H 1557 2,4-Cl2-Ph 2-Cl-Ph 0 H H H H H 1558 2,4-Cl2-Ph G-C4F9 0 H H h H H 98 --— urf.' /j, t-i ^-prfliufr-'** •*•''"' '• o o 99 234 84 1 .
Table 4 (continued) Ex.
No. A B n R si 1 si; da! 1559 2-F-Ph 4-F-Ph 0 H H H H H 1560 2-F-Ph 2,4-Cl -Ph 0 H H H H H 1561 2-F-Ph 4-Cl-Ph 0 H H H H H 1562 2-F-Ph 2,4-F2-Ph 0 H h h H H 1563 2-F-Ph 4—CF^-Ph 0 H H h H H 1564 2-F-Ph 2-F-Ph 0 H h h H h 1565 2-F-Ph 2-Cl-Ph 0 H h h h h 1566 2-F-Ph n-C4F9 0 H H H H H 1567 2,4-F2-Ph 4-F-Ph 0 H H H H H 1568 2,4-F2-Ph 2,4-Cl2-Ph 0 H H H H H 1569 2,4-F2-Ph 4-Cl-Ph 0 H H H H H 1570 2,4-F2-Ph 2,4-F2-Ph 0 H h H H H 1571 2,4-F2-Ph 4-CF3-Ph 0 H H H H H 1572 2,4-F-Ph 2-F-Ph 0 H H H H H 2 1573 2,4-F2-Ph 2-Cl-Ph 0 H H H H H 1574 2,4-F2-Ph n-C4F9 0 H H H H H 1575 Ph 4-F-Ph 0 H CH3 H H H 1576 Ph 4-F-Ph 0 -(CH 2}2" H H h 1577 Ph 4-F-Ph o ch3 CH3 H h H 1578 4-F-Ph 4-F-Ph 0 H CH3 H H H 1579 4-F-Ph 4-F-Ph 0 -(CH 2>2~ H H H 1580 4-F-Ph 4-F-Ph o ch3 ch3 H H H 1581 4-Cl-Ph 2,4-Cl2-Ph 0 H ch3 H H H 99 100 Table 4 (continued) r> Ex.
No. A B n R si S! si R 1582 4-Cl-Ph 2,4-Cl2-Ph 0 -(ch2 V h h h 1583 4-Cl-Ph 2,4-Cl2- •Ph 0 CH3 CH3 h h h 1584 2-Cl-Ph 4-Cl-Ph 0 h "S h h h 1585 2-Cl-Ph 4-Cl-Ph 0 -<ch2 V h h h 1586 2-Cl-Ph 4-Cl-Ph 0 c»3 CH3 h h H 1587 4-F-Ph 4-F-Ph 0 H C2»5 H H H 1588 4-F-Ph 4-F-Ph 0 H i-CjH [7H H H 1589 4-F-Ph 4-F-Ph 0 H n-C.H 4 9« H H 1590 4-F-Ph 4-F-Ph 0 H Ph H K H 1591 4-F-Ph 4-F-Ph 0 H t-CH 4 9« H H 1592 4-F-Ph 4-F-Ph 0 H Ph H H H 1593 4-F-Ph 4-F-Ph 0 CH3 t-CH — 4 9« H H 1594 4-F-Ph 4-F-Ph 0 CT3 Ph H H H 1595 4-F-Ph 4-F-Ph 0 -<ch2) 3~ H H H 1596 4-F-Ph 4-F-Ph 0 -(ch2) 4~ H H H 1597 4-F-Ph 4-F-Ph 0 -(ch2) " H H H 1598 4-F-Ph 4-F-Ph 0 -(ch2) 6~ H H H 1599 4-CH3-Ph 4-F-Ph 0 H CH3 H H H 1600 4-F-Ph 4-F-Ph 1 H CH3 H H H 1601 4-Cl-Ph 4-F-Ph 4 H CH3 H h H 1602 n-C.F_ - 4 9 4-F-Ph 0 h ch3 H H H 1603 (CH3)2N 4-F-Ph 1 h ch3 H H H 100 234 8 4 1 r> © 101 Table 4 (continued) Ex. No.
B 16OA 5-Cl-2-thienyl 4-F-Ph 1605 2-Cl-3-thienyl 4-F-Ph 1606 1-imidaroyl 4-F-Ph 1607 4-F-Ph 1608 4-F-Ph 1609 4-F-Ph 1610 4-F-Ph 1611 4-CF30-Ph 1612 2-Cl-Ph 1613 2-Cl-Ph 1614 2-Cl-Ph 1615 2-Cl-Ph 1616 4-Cl-Ph 1617 4-Cl-Ph 1618 4-Cl-Ph 1619 4-Cl-Ph 1620 Ph 1621 Ph 1622 Ph 1623 Ph 1624 OH 1625 OH 1626 OH 4-F-Ph 4-F-Ph 4-F-Ph 4-F-Ph 4-F-Ph 4-Cl-Ph 4-Cl-Ph 4-Cl-Ph 4-Cl-Ph n R R* gi 0 H CH3 H 0 H CH3 H 0 H CH3 H 0 H H CH, 3 4 2_ I_ M.P.'C H H H H H H H H 0 H H CH CH=CH_ H H 2 2 0 H H COCH. 0 H H CO CH_ 2 3 0 H H 0 H H H CH.
H H H H H H H H 0 H H CH2CH=CH2 H H 0 H H COCH. 0 H H CO CH. 2 3 2,4-Cl2-Ph 0 H H CH.
H H H H H H 2,4-Cl -Ph 0 H H CH_CH=CH, H H 2,4-Cl2-Ph 0 H H 2,4-Cl2-Ph 0 H H 2 COCH.
CO.CH. 2 3 4-F-Ph 4-F-Ph 4-F-Ph 4-F-Ph 0 H H CH.
H H H H H H 0 H H CH2CH«CH2 H H 0 H H COCH. 0 H H COCH 2 3 2,4-Cl2-Ph 2 H H H 2,4-Cl2-Ph 3 H H H 2,4-Cl2-Ph 4 H H H H H H H H H H H H H 101 C: 102 1 f )'• Table 4 (Continued) Ex.
No. A B n R R' l_& 2 _ R li 1627 1-imidazoyl 2,4-Cl2-Ph 1 H H H H H 1628 1-imidazoyl 2,4-Cl2-Ph 2 H H H H H 1629 1-imidazoyl 4-F-Ph 3 H H H H H 1630 1-imidazoyl 4-F-Ph 4 H H H H H 1631 1H-1,2,4-triazoyl-l- -yl 4-F-Ph 1 H H H H H 1632 1H-1,2,4-triazoyl- -1-yl 4-F-Ph 2 H H H H H 1633 1H-1,2,4-triazoyl- •yl 4-F-Ph 3 H H H H H 1634 1H-1,2,4-triazoyl-l-yl 4-F-Ph 4 H H H H H 1635 1H-1,2,4-triazoyl-l-yl 2,4-Clj-Ph 1 H H H H H 1636 Ph ' 2,5-F2-Ph 0 H H H H H 1637 Ph 3-F-Ph 0 H H H H H 1638 Ph 2,5-Cl2-Ph 0 H H H H H 1639 Ph 3-Cl-Ph 0 H H H H H 1640 Ph 4-Br-Ph 0 H H H H H 1641 Ph 4-I-Ph 0 H H H H H 1642 Ph 3,4-F2-Ph 0 H H H H H 1643 Ph 3,4-Cl2-Ph 0 H H H H H 1644 Ph 2,6-Cl2-Ph 0 H H H H H 1645 Ph 2-Cl-(4-F)-Ph 0 H H H H H 1646 Ph 2,4,6-Cl -Ph 0 H H H H H 234 84 1 1647 Ph 2-F-(4-Cl)-Ph 0 H H H H H 1648 Ph Ph 0 H H H H H 1649 Ph 4-CH^-Ph 0 H H H H H 1650 Ph 3-CHj-Ph 0 H H H H H 1651 Ph 2-CH3-Ph 0 H H H H H 1652 Ph 2-CF3-Ph 0 H H H H H 1653 Ph 3-CF3-Ph 0 H H H H H 102 #«"f!rst!: tr>Wv-v^'wiiyi ft '■ * .., ^tr-*'1 234 84 1 103 Table 4 (Continued) o c v/ Ex. Ko.
B ,1 -2 3 _4 1654 Ph 2-F-(4-CF3)-Ph 0 H H H H H 1655 Ph 4-CH30-Ph 0 H H H H H 1656 Ph -Cl-2-pyridyl 0 H H H H H 1657 Ph -Cl-2-thienyl 0 H H H H H 1658 Ph 2-C1-3-thienyl 0 H H H H H 1659 Ph -C4H9 0 H H H H H 1660 2-Cl-Ph 2,5-F2-Ph 0 H H H H H 1661 2-Cl-Ph 3-F-Ph 0 H H H H H 1662 2-Cl-Ph 2,5-Cl2-Ph 0 H H H H H 1663 2-Cl-Ph 3-Cl-Ph 0 H H H H H 1664 2-Cl-Ph 4-Br-Ph 0 H H H H H 1665 2-Cl-Ph 4-I-Ph 0 H H H H H 1666 2-Cl-Ph 3,4-F2-Ph 0 H H H H H 1667 2-Cl-Ph 3,4-Cl2-Ph 0 H H H H H 1668 2-Cl-Ph 2,6-Cl2-Ph 0 H H H H H 1669 2-Cl-Ph 2-C1-(4-F)-Ph 0 H H H H H 1670 2-Cl-Ph 2,4,6-Cl3-Ph 0 H H H H H 1671 2-Cl-Ph 2-F-(4-Cl)-Ph 0 H H H H H 1672 2-Cl-Ph Ph 0 H H H H H 1673 2-Cl-Ph 4-CH3-Ph 0 H H H H H 1674 2-Cl-Ph 3-CH3-Ph 0 H H H H H 1675 2-Cl-Ph 2-CH3-Ph 0 H H H H H 1676 2-Cl-Ph 2-CF3-Ph 0 H H H H H 1677 2-Cl-Ph 3-CF3-Ph 0 H H H H H 1678 2-Cl-Ph 2-F-(4-CF3)-Ph 0 H H H H H 1679 2-Cl-Ph 4-CH30-Ph 0 H H H H H 103 """wjtssg<*§,: ? V?.'' ; '\v k * v1 j . ?i i ■1 n n Ex. Mo. 1680 2-Cl-Ph 1681 2-Cl-Ph 1682 2-Cl-Ph 1683 3-Cl-Ph 234 84 1 104 Table 4 (Continued) B -Cl-2-pyridyl 5-C1-2-thienyl 2-C1-3-thienyl 2,5-F2-Ph o =2 „3 4u „ n R R R R R M.P. *C 0 H H H H H 0 H H H H H 0 H H H H H 0 H H H H H 1684 3-Cl-Ph 2,5-Cl2-Ph 0 H H H H H 1685 4-F-Ph 2,5-F2-Ph 0 H H H H H 1686 4-F-Ph 3-F-Ph 0 H H H H H 1687 4-F-Ph 2,5-Cl2-Ph 0 H H H H H 1688 4-F-Ph 3-Cl-Ph 0 H H H H H 1689 4-F-Ph 4-Br-Ph 0 H H H H H 1690 4-F-Ph 4-I-Ph 0 H H H H H 1691 4-F-Ph 3,4-F2-Ph 0 H H H H H 1692 4-F-Ph 3,4-Cl2-Ph 0 H H H H H 1693 4-F-Ph 2,6-Cl2-Ph 0 H H H H H 1694 4-F-Ph 2-Cl-(4-F)-Ph 0 H H H H H 1695 4-F-Ph 2,4,6-Cl3-Ph 0 H H H H H 1696 4-F-Ph 2-F-(4-Cl)-Ph 0 H H H H H 1697 4-F-Ph Ph 0 H H H H H 1698 4-F-Ph 4-CH3-Ph 0 H H H H H 1699 4-F-Ph 3-CH3-Ph 0 H H H H H 1700 4-F-Ph 2-CH3-Ph 0 H H H H H 1701 4-F-Ph 2-CF3-Ph 0 H H H H H 1702 4-F-Ph 3-CF3-Ph 0 H H H H H 1703 4-F-Ph 2-F-(4-CF )-Ph 0 H H H H H 104 jti 23 4 8 4 1 105 Table 4 (Continued) Ex. No. n O 1704 4-F-Ph 1705 4-F-Ph 1706 4-F-Ph 1707 4-F-Ph 1708 3-F-Ph 1709 3-F-Ph 1710 4-Cl-Ph 1711 4-Cl-Ph 1712 4-Cl-Ph 1713 4-Cl-Ph 1714 4-Cl-Ph 1715 4-Cl-Ph 1716 4-Cl-Ph 1717 4-Cl-Ph 1718 4-Cl-Ph 1719 4-Cl-Ph 1720 4-Cl-Ph 1721 4-Cl-Ph 1722 4-Cl-Ph 1723 4-Cl-Ph 1724 4-Cl-Ph 1725 4-Cl-Ph 1726 4-Cl-Ph 1727 4-Cl-Ph 1728 4-Cl-Ph 1729 4-Cl-Ph 1730 4-Cl-Ph 4-CH^O-Ph -Cl-2-pyridyl 2-Cl-3-thienyl 5-Cl-2-thienyl 2,5-Cl2-Ph 2,5-F2-Ph 2,5-F2-Ph 3-F-Ph 2.5-Cl2-Ph 3-Cl-Ph 4-Br-Ph 4-I-Ph 3,4-F2-Ph 3,4-Cl2-Ph 2.6-Cl2-Ph 2-Cl-(4-F)-Ph 2,4,6-Cl3-Ph 2-F-(4-Cl)-Ph Ph 4-CH3-Ph 3-CH3-Ph 2-CH3-Ph 2-CF3-Ph 3-CFj-Ph 2-F-(4-CF3)-Ph 4-CH30-Ph -Cl-2-pyridyl 12 3 4 n R R~ FT_ R_ R_ M.P.'C 0 H H H H H 0 H H H H H 0 H H H H H 0 H H H H H 0 H H H H H 0 H H H H H 0 H H H H H 0 H H H H H 0 H H H H H 0 H H H H H 0 H H H H H 0 H H H H H 0 H H H H H 0 H H H H H 0 H H H H H 0 H H H H H 0 H H H H H 0 H H H H H 0 H H H H H 0 H H H H H 0 H H H H H 0 H H H H H 0 H H H H H 0 H H H H H 0 H H H H H 0 H H H H H 0 H H H H H 105 KMW.^ . .. „_i._ , r> o \jy 234 84 1 106 Table 4 (Continued) Ex.
No. A B nH 2R3R 1731 4-Cl-Ph -C1-2-thienyl 0 H H H H H 1732 4-Cl-Ph 2-Cl-3-thienyl 0 H H H H H 1733 4-Cl-Ph CH2 '^'C H.-4F 6 4 0 H H H H H 1734 4-Cl-Ph t-butyl 0 H H H H H 1735 4-Cl-Ph n-hexyl 0 H H H H H 1736 4-Cl-Ph n-heptyl 0 H H H H H 1737 4-Cl-Ph n-octyl 0 H H H H H 1738 4-Cl-Ph -C F 6 13 0 H H H H H 1739 4-Cl-Ph -C F 8 17 0 H H H H H 1740 4-Cl-Ph 4-pyridyl 0 H H H H H 1741 4-Cl-Pb 2-pyridyl 0 H H H H H 1742 4-Cl-Ph 2-thienyl 0 H H H H H 1743 4-Cl-Ph 4-n-Bu-Ph 0 H H H H H 1744 4-Cl-Ph 4-n-Bu0-Ph 0 H H H H H 1745 4-Cl-Ph -CF3-2-pyridyl 0 H H H H K 1746 4-Cl-Ph -CH3S02-2-thienyl 0 H H H H H 174 7 4-C2H5-Ph 4-F-Ph 0HH H H H 1748 4-(n-Bu0)-Ph 4-F-Ph 0 H H H H H 1749 2-CH_S0_-iraida-3 2 4-F-PH 0 H H H H H zol-l-yl 1750 5-CH3S-l,2,4- 4-F-Ph 0 H H H H H triarol-l-yl 1751 "C6F13 4-F-Ph 0 H H H H H 1752 -°8F17 4-F-Ph 0 H H H H H 1753 3-CH30-Ph 4-F-Ph 0 H H H H H 106 -. - *„,,..--„-«.™..~--.= 107 Table 4 (Continued) Ex.
Ho. A 1754 2-CF3-imidazol-l-yl 1755 4-(i-C3H?0)-Ph 1756 4-I-Ph 1757 3,4-F2-Ph 1758 3,4-Cl2-Ph 1759 2,6-Cl2-Ph 1760 2-Cl-(4-F)-Ph 1761 2,4,6-Cl3-Ph 1762 4-CH3-Ph 1763 3-CH3-Ph 1764 2-CH3-Ph 1765 2-CF -Ph 3 1766 3-CF3-Ph 1767 4-CH30-Ph 1768 2,3-Cl2-Ph 1769 3,5-Cl2-Ph 1770 2,5-Cl2-Ph 1771 3-Br-Ph 1772 4-CH0-Ph 2 5 1773 2,4-(CH3)2-Ph 1774 2,4,6-(CH3)3-Ph 1775 4-Ph-Ph 1776 5-Cl-2-thienyl 1777 2-C1-3-thienyl B n R R1 R4 4-F-Ph 0 H H H H H 4-F-Ph 0 H H H H H 4-F-Ph 0 H H H H H 4-F-Ph 0 H H H K H 4-F-Ph 0 H H H H H 4-F-Ph 0 H H H H H 4-F-Ph 0 H H H H H 4-F-Ph 0 H H H H H 4-F-Ph 0 H H H H H 4-F-Ph 0 H H H H H 4-F-Ph 0 H H H H H 4-F-Ph 0 H H H H H 4-F-Ph 0 H H H H H 4-F-Ph 0 H H H H H 4-F-Ph 0 H H H H H 4-F-Ph 0 H H H H H 4-F-Ph 0 H H H H H 4-F-Ph 0 H H H H H 4-F-Ph 0 H H H H H 4-F-Ph 0 H H H H H 4-F-Ph 0 H H H H H 4-F-Ph 0 H H H H H 4-F-Ph 0 H H H H H 4-F-Ph 0 H H H H H 107 234 8 4 1 108 Table 4 (Continued) Ex.
No. A B n R R i; R; 2 3 4 R R M.P *C o 17 78 1-imidazoyl 4-F-Ph 0 H H H H H 1779 lH-l,2,4-triazoyl- •1-yl 4-F-Ph 0 H H H H H 1780 2-pyridyl 4-F-Ph 0 H H H H- H 1781 5-Cl-2-pyridyl 4-F-Ph 0 H H H H H o 1782 3-pyridyl 4-F-Ph 0 H H H H H 1783 4-pyridyl 4-F-Ph 0 H H H K H 1784 n-C.F. - 4 9 4-F-Ph 0 H H H K H 1785 4-I-Ph 2,4-Cl2-Ph 0 H H H H H 1786 3,4-F2-Ph 2,4-Cl2-Ph 0 H H H H H 1787 3,4-Cl2-Ph 2,4-Cl2-Ph 0 H H H H H 1788 2,6-Cl2-Ph 2,4-Cl2-Ph 0 H H H H H 1789 2-Cl-(4-F)-Ph 2,4-Cl2-Ph 0 H H H H H 1790 2,4,6-Cl3-Ph 2,4-Cl2-Ph 0 H H H H H 1791 4-CH3-Ph 2,4-Cl2~Ph 0 H H H H H 1792 3-CH3-Ph 2,4-Cl2-Ph 0 H H H H H 1793 2-CH3-Ph 2,4-Cl -Ph 0 H H 2 H H H o 1794 2-CF3-Ph 2,4-Cl2-Ph 0 H H H H H 1795 3-CF3-Ph 2,4-Cl2-Ph 0 H H H H H 1796 4-CH30-Ph 2,4-Cl2-Ph 0 H H H H H # 1797 2,3-Cl2-Ph 2,4-Cl2-Ph 0 H H H H H 1798 3,5-Cl -Ph 2,4-Cl -Ph O H H H H H 1799 2,5-Cl2-Ph 2,4-Cl2-Ph 0 H H H H H 1800 3-Br-Ph 2,4-Cl2~Ph 0 H H H H H 1801 4-C^O-Ph 2,4-Cl2-Ph 0 H H H H H 35 1802 2,4-(CH3)2-Ph 2,4-Cl2~Ph 0 H H H H H 108 234 84 1 109 Table 4 (Continued) Ex. mo. a b n r r! h.p.'c 1803 2,4,6-(CH3)3-Ph 2,4-Cl2-Ph 0 H H H H H 1804 4-Ph-Ph 2,4-Cl2-Ph 0 H H H H H 1805 5-Cl-2-thienyl 2,4-Cl2-Ph 0 H H H H H 1806 2-Cl-3-thienyl 2,4-Cl2-Ph 0 H H H H H 10 1807 1-imidazoyl 2,4-Cl2-Ph 0 H H H H H 1808 1H-1,2,4-triazoyl-l-yl 2,4-Cl2-Ph 0 H H H H H 1809 2-pyridyl 2,4-Cl2-Ph 0 H H H H H 1810 5-Cl-2-pyridyl 2,4-Cl2~Ph 0 H H H H H 1811 3-pyridyl 2,4-Cl2~Ph 0 H H H H H 1812 4-pyridyl 2,4-Cl2-Ph 0 H H H H H 1813 H-C4F9 2,4-Cl2-Ph 0 H H H H H 1814 4-I-Ph 4-Cl-Ph 0 H H H H H 1815 3,4-F2-Ph 4-Cl-Ph 0 H H H H H 1816 3,4-Cl2-Ph 4-Cl-Ph 0 H H H H H 1817 2,6-Cl2-Ph 4-Cl-Ph 0 H H H H H 1818 2-Cl-(4-F)-Ph 4-Cl-Ph 0 H H H H H 1819 2,4,6-Cl3-Ph 4-Cl-Ph 0 H H H H H 1820 4-CH3-Ph 4-Cl-Ph 0 H H H H H 1821 3-CH3-Ph 4-Cl-Ph 0 H H H H H 3Q 1822 2-CH3-Ph 4-Cl-Ph 0 H H H H H 1823 2-CF3-Ph 4-Cl-Ph 0 H H H H H 1824 3-CF3-Ph 4-Cl-Ph 0 H H H H H 1825 4-CH30-Ph 4-Cl-Ph 0 H H H H H 109 234841 o r>.
G 10 110 Table 4 (Continued) No. A B n R R 1 R2 R3 R4 M.P.*C 1826 2,3-Cl2-Ph 4-Cl-Ph 0 H H H H H 1827 3,5-Cl2-Ph 4-Cl-Ph 0 H H H H H 1828 2,5-Cl2-Ph 4-Cl-Ph 0 H H H H H 1829 3-Br-Ph 4-Cl-Ph 0 H H H H H 1830 4-EtO-Ph 4-Cl-Ph 0 H H H H H 1831 2,4-(CH3)2-Ph 4-Cl-Ph 0 H H H H H 1832 2,4,6—(CH ) -Ph j j 4-Cl-Ph 0 H H H H H 1833 4-Ph-Ph 4-Cl-Ph 0 H H H H H 1834 5-Cl-2-thienyl 4-Cl-Ph 0 H H H H H 1835 2-Cl-3-thienyl 4-Cl-Ph 0 H H H H H 1836 1-imidazoyl 4-Cl-Ph 0 H H H H H 1837 1H-1,2,4-triazoyl-l-yl 4-Cl-Ph 0 H H H H H 1838 2-pyridyl 4-Cl-Ph 0 H H H H H 1839 5-Cl-2-pyridyl 4-Cl-Ph 0 H H H H H 1840 3-pyridyl 4-Cl-Ph 0 H H H H H 1841 4-pyridyl 4-Cl-Ph 0 H H H H H 1842 n-C F "49 4-Cl-Ph 0 H H H H H 1843 4-I-Ph 2,4-F2-Ph 0 H H H H H 1844 3,4-F2-Ph 2,4-F2-Ph 0 H H H H H 1845 3,4-Cl2-Ph 2,4-F2-Ph 0 H H H H H 1846 2,6-Cl2-Ph 2,4-F2-Ph 0 H H H H K 1847 2-Cl-(4-F)-Ph 2,4-F2-Ph 0 H H H H H 1848 2,4,6-Cl3-Ph 2,4-F2-Ph 0 H H H H H 1849 4-CH3-Ph 2.4-F2-Ph 0 H H H H H 1850 3-CH3-Ph 2,4-F2-Ph 0 H H H H H 110 234 84 1 G in Table 4 (Continued) Ex.
No^ A B n R R1 R2 R3 R4 H.P.'C 1851 2-CH3-Ph 2,4-F2-Ph 0 H H H H H 1852 2-CF3-Ph 2,4-F2-Ph 0 H H H H H 1853 3-CF3-Ph 2,4-F2-Ph 0 H H H H H 1854 4-CH30-Ph 2,4-F2-Ph 0 H H H H H 1855 2,3-Cl2-Ph 2,4-F2-Ph 0 H H H K H 1856 3,5-Cl2-Ph 2,4-F2-Ph 0 H H H H H 1857 2,5-Cl2-Ph 2,4-F2-Ph 0 H H H H H 1858 3-Br-Ph 2,4-F2-Ph 0 H H H H H 1859 4-C2H50-Ph 2,4-F2-Ph 0 H H H H H 1860 2,4-(CH3)2-Ph 2,4-F2-Ph 0 H H H H H 1861 2,4,6-(CH3)3-Ph 2,4-F2-Ph OHH H H H 1862 4-Ph-Ph 2,4-F_-Ph OHH H H H z 1863 5-C1-2-thienyl 2,4-F2-Ph OHH H H H 1864 2-Cl-3-thienyl 2,4-F2-Ph OHH H H H i865 1-imidaroyl 2,4-F2-Ph OHH H H H 1866 1H-1,2,4-triazoyl-l-yl 2,4-F2-Ph OHH H H H 1867 2-pyridyl 2,4-F2-Ph OHH H H H 1868 5-Cl-2-pyridyl 2,4-F2-Ph OHH H H K 1869 3-pyridyl 2,4-F2-Ph OHH H H H 1870 4-pyridyl 2,4-F2-Ph OHH H H H 1871 n-C4Fg 2,4-F2-Ph OHH H H H 111 234 84 1 n- o' 112 Table 4 (Continued) Ex. Wo.
A B n R R si R4 1872 4-F-Ph 4-F-Ph OHH h ch3 H 1873 4-F-Ph 4-F-Ph OHH H CH3 CH3 1874 4-F-Ph 4-F-Ph OHH H F H 1875 4-F-Ph 4-F-Ph OHH H F CH3 1876 4-F-Ph 4-F-Ph OHH H F F 1877 4-Cl-Ph 2,4-Cl2- -Ph OHH H CH3 H 1878 4-Cl-Ph 2.4-Cl2- -Ph OHH H CH3 CH3 1879 4-Cl-Ph 2.4-Cl2- -Ph OHH H F H 1880 4-Cl-Ph 2.4-Cl2- -Ph OHH H F OT3 1881 4-Cl-Ph 2,4-Cl2- ■Ph OHH H F F 1882 2-Cl-Ph 4-Cl-Ph OHH H CH3 H 1883 2-Cl-Ph 4-Cl-Ph OHH H CH3 OT3 1884 2-Cl-Ph 4-Cl-Ph OHH H F H 1885 2-Cl-Ph 4-Cl-Ph OHH H F CH3 1886 2-Cl-Ph 4-Cl-Ph OHH H F F 1887 Ph 4-F-Ph OHH H ch3 H 1888 Ph 4-F-Ph OHH H ch3 CH3 1889 Ph 4-F-Ph OHH H F h 1890 Ph 4-F-Ph OHH h F ch3 1891 Ph 4-F-Ph OHH H F F H.P.'C 112 \ J, , Sl^L" '■",. ., • ;.y- _ 23 4 84 1 n> i w 113 Pharmaceutical Utility In vitro activity (Table 5) is expressed in terms of the minimal inhibitory concentration (MIC) of the test compound which inhibits the growth of yeasts 5 and fungi.
The target organisms. Candida albicans ATCC 11651 and Aspergillus fumiaatus ATCC 28214 are standardized. [V. Bezjak, J. Clinical Micro.. 21 509-512 (1984)] to a concentration of 107 10 organisms/ml and maintained at -70° until use. Test compounds are solubilized in dimethyl sulfoxide (DMSO) and diluted in Eagle's Minimum Essential Medium (EMEM) broth to achieve a final concentration of 200 vg/ml. Stock solutions of standard antifungal 15 agents are stored at -70° and diluted in EMEM as required.
The in vitro assay utilizes a microtiter broth dilution technique [L. Polonelli and G. Morace, Mycopatholoqia. 86. 21-28 (1984)] and C. Hughes. 20 et. al. Antimicrob. Act, and Chemo.. 25. 560-562(1984)]. Test compounds are serially diluted in EMEM to give graded concentrations ranging from 100 to 0.4 vg/nil. The appropriate wells are inoculated with the required 4 organism (C. albicans at 1 x 10 organisms/ml and 25 A. fumigatus at 5 x 105 organisms/ml) and the assay incubated at 30° for 24 hours. The extent of fungal growth is determined at an optical density equal to 540 nm using a scanning spectrophotometer (Flow® MCC) and MIC values, representing the minimal 30 concentration of a compound which inhibited growth, are determined. [V. Grenta. et al. Antimicrob. Aq. and Chemo.. 22. 151-153 (1982)]. 113 v.,, 234 84 1 \gn_^*r 114 The in vivo activity of test compounds is based on the percent (\) survival of infected animals receiving te6t or standard agent compared to that in an infected untreated group (Table 6). The in vivo 5 assays are chronic systemic infections lethal to mice within 7 days post infection. [J- Barnes, et al. Lab Investigation. 49 460-467 (1963). and T. Rogers and E. Balish. Infection and Immunity. 14 33-38 (1976)].
Candida albicans ATCC 11651. from a frozen 9 stock culture (10 organisms/ml) maintained at -70°. n is diluted in saline to 1 x 10 organisms/ml and 0.2 ml inoculated intravenously (caudal vein) into 20.0 gm CF-1 female mice (Charles River).
Test compounds are routinely solubilized in 15 0.25\ (w/v) methylcellulose (Methocel®) but for those compounds difficult to solubilize 10* (w/v) Gmulophor® (EL620 GAF Corp.) is used. The standard antifungal agents, amphotericin B (Fungizone®) in water and ketoconazole (Nizoral®) in Methocel®. 20 are administered at 1.0 mg/kg/day and 150 mg/kg/day. respectively.
In a primary assay, mice (10 per group) are infected with C. albicans. and receive test compounds at 50 or 150 mg/kg/day via the subcutaneous route. 25 Animals are dosed with the test compound at 1 and 6 hour post-infection and then once daily for the next three days. Survival of mice in each group is recorded for 21 days.
Compounds which protect >70* of the infected 30 animals for 14 days at a dose 150 mg/kg/day or less are viewed as active. 114 2 3 4 8 4 1 115 Table 5 In Vitro Antifungal Results C V 5 CRR _ , Q \ OR E Y" f a-(chj)n-c c—< j Example MIC values (ug/ml) Number C. albicans A. furoiqatus 1 <0.01 6.3 1 HCl salt 0.05 12.5 2 <0.4 1.6 3 <0.4 50 4 0.03 0.8 6 1.6 25 1.6 25 15 0.1 50 16 0.03 6.3 17 0.03 12.5 1.6 25 26 <0.4 12.5 25 26 HCl salt 0.03 0.4 27 <0.4 12.5 28 0.03 1.6 32 <0.4 1.6 33 0.03 0.03 30 34 0.03 3.2 34 HCl salt 0.03 1.6 0.03 0.1 35 HCl salt 0.03 <0.2 39 0.4 25 40 0.4 3.2 115 Hill o ' 116 Table 5 (Continued) 23 4 84 t O Example Number 41 42 • 47 49 50 51 52 52 HCl salt 65 67 B 5 94 99 100 101 114 117 163 164 170 177 208 286 291 359 360 361 363 447 449 MIC values (tig/ml) C. albicans A. fumiqatus 0.4 0.03 0.03 0.03 0.1 0.03 0.03 0.03 0.2 0.03 <0.4 0.4 0.05 0.03 0.03 0.4 0.4 0.03 0.03 1.6 3.2 1.6 0.4 0.2 0.4 0.8 0.8 100 3.2 <0.4 50 6.3 1.6 12.5 0.8 3.2 0.4 0.4 100 100 12.5 50 6.3 3.2 12.5 50 100 12.5 1.6 100 >100 50 25 100 50 100 25 100 N.T. N.T. 116 -V, 234 84 1 117 Table 5 (Continued) Example Number MIC values (ng/ral) 450 >100 N.T. 451 12.5 N.T. 452 >100 N.T. 453 1.6 >100 454 100 >100 455 N.T. 477 >100 N.T. 594 0.8 0.8 594 HCl salt 0.03 0.4 596 0.05 0.4 603 0.1 >100 605 0.2 100 608 0.4 6.3 620 0.03 0.05 622 0.03 0.1 627 0.03 644 0.03 0.4 646 0.03 0.4 651 0.8 100 656 <0.4 12.5 657 0.4 100 661 1.6 100 667 6.3 668 0.4 50 669 0.03 0.8 671 0.03 0.2 675 0.1 685 0.8 100 699 50 100 721 0.4 12.5 117 j \ I 0 234 84 1 118 Table 5 (Continued) Example Number MIC values (vg/ral) C. albicans A. fumiqatus 724 0.4 0.4 726 0.8 6.3 815 0.03 >100 905 0.04 100 1258 1.6 >100 1260 0.8 >100 1276 0.03 1.6 1276a 3.2 100 1277 0.03 6.3 1277 HCl salt 0.03 3.2 1277a 6.3 100 1278 <0.4 >100 1300 <0.4 6.3 1377 1.6 100 1451 >100 >100 1459 >100 >100 1487 0.4 6.3 1527 0.4 6.3 Standards* Amphotericin B Nystatin -Fluorocytosine Ketoconazole Miconazole 0.33+0.2 1.3+0 0.14+0.1 <0.1 <0.1 1.4+0.5 3.0+1.0 5.7+4.0 11.0+5.0 1.3 + 0 •MIC values of the standard drugs are the mean of five determinations + Standard deviation 118 o o 119 TABLE 6 In Vivo Antifungal Results * Survival (150 mg/kg per day) Primary Assay EX.
Days NO. 7 14 21 1 100 100 80 2 100 100 80 3 100 100 60 4 100 50 N.T. 6 50 0 0 100 90 60 16 100 100 100 17 100 90 70 100 100 50 26 100 100 100 26 salt 100 90 80 27 100 100 100 28 100 90 N.T. 32 100 90 50 33 100 100 100 34 100 100 100 34 salt 100 100 100 100 100 90 salt 100 100 70 39 100 80 N.T. 40 100 100 N.T. 41 100 100 N.T. 42 80 80 50 47 90 80 49 100 90 60 50 • 100 90 50 51 100 100 80 52 100 100 90 52 salt 100 100 90 55 100 70 50 65 100 70 50 67 100 100 100 85 100 80 70 94 100 40 99 100 100 40 100 100 50 101 100 90 60 114 70 117 60 0 0 163 90 60 40 234 119 ^ aX' • 120 TABLE 6 (continued) 234 84 1 In Vivo Antifungal Results n Ex. No. 164 208 286 359 360 361 363 453 594 596 603 608 620 622 627 644 646 651 656 657 661 667 668 669 671 675 685 721 724 725 726 905 1276 1276a 1277 1277a 1278 1487 1527 * Survival (150 mg/kg per Primary Assay 100 0 100 100 100 100 10 60 70 70 10 100 100 100 0 80 100 100 100 0 50 10 70 100 100 100 30 100 100 90 100 80 100 0 100 80 0 100 100 Day6 14 80 0 50 80 60 100 0 40 10 60 0 70 100 100 0 70 100 50 90 0 20 0 10 100 100 60 10 30 90 90 80 50 70 0 100 0 0 100 70 day) 21 70 0 20 80 40 90 0 30 0 40 0 20 90 100 0 50 70 20 40 0 0 0 0 100 60 0 0 30 40 40 10 20 50 0 90 0 0 70 20 120 fts'ivssv'w-n -Vs..-. 234 84 1 Standards Amphotericin B 100 Ketoconazole 100 N.T.: Not Tested 121 100 80 100 50 o 121 P ' 23 4 8 4 1 0 122 DOSAGE FORMS The antiraycotic agents of formula I can be administered by any means that effects contact of the active ingredient with the agent's site of action in ^ 5 the body. The compounds can be administered by any conventional means available for use in conjunction with pharmaceuticals, either as individual therapeutic agents or in a combination of therapeutic agents. | They can be administered alone, but are generally s 10 administered with a pharmaceutical carrier selected on the basis of the chosen route of administration and standard pharmaceutical practice.
The dosage administered will, of course, vary depending on the use and known factors such as the \ 15 pharmacodynamic characteristics of the particular agent, and its mode and route of administration: age, health, and weight of the recipient: nature and extent of symptoms, kind of concurrent treatment, frequency of treatment, and the effect desired. 1 20 Dosage forms (compositions) suitable for ; administration contain from about 200 milligram to about 2000 milligrams of active ingredient per unit. i In these pharmaceutical compositions, the active ingredient will ordinarily be present in an amount of 25 about 0.5-95* by weight based on the total weight of the composition. For use in the treatment of said diseases, a daily dose of active ingredient can be about 10 to 50 milligrams per kilogram of body weight. ^|j! The composition may be in a conventional pharmaceutical form suitable for oral administration, for example a tablet, a capsule, an emulsion or an aqueous or oily solution or suspension, or suitable for topical application, for example a cream, ointment or gel. It can also be administered 35 parenterally in 6terile liquid dosage forms. 122 234841 O 123 Gelatin capsules contain the active ingredient and powdered carriers, such as lactose, starch, cellulose derivatives, magnesium stearate. stearic acid and the like. Similar diluents can be U6ed to f~~\ 5 make compressed tablets. Both tablets and capsules can be manufactured as sustained release products to provide for continuous release of medication over a period of hours. Compressed tablets can be sugar coated or film coated to mask any unpleasant taste and 10 protect the tablet from the atmosphere, or enteric coated for selective disintegration in the gastrointestinal tract.
The pharmaceutical compositions which are ointments, creams and gels can, for example, contain 15 the usual diluents, e.g. animal and vegetable fats, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones. bentonites. silicic acid, talc and zinc oxide or mixtures of these substances.
In general, water, a suitable oil, saline, aqueous dextrose (glucose), and related sugar solutions and glycols such as propylene glycol or polyethylene glycols are suitable carriers for parenteral solutions. Solutions for parenteral 25 administration preferably contain a water soluble salt of the active ingredient, suitable stabilizing agents. and if necessary, buffer substances. Antioxidizing agents such as sodium bisulfite, sodium sulfite, or iflEk ascorbic acid, either alone or combined, are suitable stabilizing agents.
All the pharmaceutical compositions can also contain coloring and flavoring to increase patient acceptance.
Also used are citric acid and its 6alts and 35 sodium EDTA. In addition, parenteral solutions can 123 r^ 234841 124 contain preservatives, such as benzalkonium chloride. methyl or propyl-paraben, and chlorobutanol.
Suitable pharmaceutical carriers are described in Remington's Pharmaceutical Sciences. A. Osol. a 5 standard reference text in this field.
Useful pharmaceutical dosage forms for | administration of the compounds of "formula I . can j be illustrated as follows: Capsules (3 A large number of unit capsules are prepared by filling standard two-piece hard gelatin capsules each with 100 milligrams of powdered active ingredient, 150 milligrams of lactose. 50 milligrams of cellulose, and 6 milligrams magnesium stearate.
Soft Gelatin Capsules A mixture of active ingredient in a digestable oil such as soybean oil. cottonseed oil or olive oil is prepared and injected by means of a positive displacement pump into gelatin to form soft gelatin 20 capsules containing 100 milligrams of the active ingredient. The capsules are washed and dried.
Tablets A large number of tablets are prepared by Hp conventional procedures so that the dosage unit is 100 milligrams of active ingredient. 0.2 milligrams of colloidal silicon dioxide. 5 milligrams of magnesium stearate. 275 milligrams of microcrystalline cellulose. 11 milligrams of starch and 98.8 milligrams fy of lactose. Appropriate coatings may be applied to increase palatability or delay absorption.
Injectable A parenteral composition suitable for administration by injection is prepared by stirring 1.5* by weight of active ingredient in 10* by volume 35 propylene glycol. The solution is made to volume with water for injection and sterilized. 124 .. x-;. :: < ..... 234 84 1 125 Suspension An aqueous suspension is prepared for oral administration so that each 5 milliliters contain 100 milligrams of finely divided active ingredient. 100 c. 5 milligrams of sodium carboxymethyl cellulose. 5 milligrams of sodium benzoate, 1.0 gram6 of sorbitol solution, U.S.P.. and 0.025 milliliters of vanillin.
Cream A cream for topical application is prepared by 10 incorporating 100 milligrams of the finely pulverized active ingredient in 5 grams of a cream base which comprises 40* white petrolatum, 3* microcrystalline wax. 10* lanolin, 5* Span®20, 0.3* Tween®20 and 41.7* water. 125 234 84 1 126 Agricultural Formulations The compounds of formula I when used for agricultural purposes will generally be used in formulation with a liquid or solid diluent or with an 5 organic solvent. Useful formulations of the compounds of Formula I can be prepared in conventional ways.
They include dU6ts. granules, pellets, solutions, emulsions, wettable powders, eraulsifiable concentrates and the like. Many of these may be applied directly. 10 Sprayable formulations can be extended in suitable media and used at spray volumes of from about one to several hundred liters per hectare. High strength compositions are primarily used as intermediates for further formulation. The formulations, broadly. 15 contain about 1* to 99* by weight of active ingredient(s) and at least one of a) about 0.1* to 35* surfactant(s) and b) about 5* to 99* solid or liquid inert diluent(s). More specifically, they will contain these ingredients in the following approximate 20 proportions: Percent by Weight Active Ingredient Diluentfs) Surfactant(s) Wettable Powders 20-90 0-74 1-10 Oil Suspensions. 5-50 40-95 0-35 Emulsions. Solutions, (including Eraulsifiable Concentrates) Aqueous Suspensions 10-50 40-84 1-20 Dusts 1-25 70-99 0-5 Granules and Pellets 1-95 5-99 0-15 High Strength 90-99 0-10 0-2 Compositions Lower or higher levels of active ingredient can. of course, be present depending on the intended use 35 and the physical properties of the compound. Higher ratios of surfactant to active ingredient are sorae- 126 o a ' 234 84 1 127 times desirable, and are achieved by incorporation into the formulation or by tank mixing.
Typical solid diluents are described in Watkins, et al.. "Handbook of Insecticide Dust Diluents and 5 Carriers". 2nd Ed., Dorland Book6. Caldwell, New Jersey. The more absorptive diluents are preferred for the wettable powders and the denser ones for du6ts. Typical liquid diluents and solvents are described in Marsden, "Solvents Guide." 2nd Ed., 10 Interscience, New York, 1950. Solubility under 0.1* is preferred for suspension concentrates; solution concentrates are preferably stable against phase separation at 0°C. "HcCutcheon's Detergents and Eraulsifiers Annual". MC Publishing Corp.. Ridgewood. 15 New Jersey, as well as Sisely and Wood. "Encyclopedia of Surface Active AgentB". Chemical Publ. Co.. Inc., New York. 1964. list surfactants and recommended uses. All formulations can contain minor amounts of additives to reduce foam, caking, corrosion, microbio-20 logical growth, etc. Preferably, ingredients should be approved by the U.S. Environmental Protection Agency for the use intended.
The methods of making such compositions are well known. Solutions are prepared by simply nixing the 25 ingredients. Fine solid compositions are made by blending and. usually, grinding as in a hammer or fluid energy mill. Suspensions are prepared by wet milling (see. for example. Littler. U.S. Patent 3.060.084). Granules and pellets may be made by 30 spraying the active material upon preformed granular carriers or by agglomeration techniques. See J. E. Browning, "Agglomeration". Chemical Engineering. Dec. 4, 1967, pp. 147ff. and "Perry's Chemical Engineer's Handbook", 4th Edn.. McGraw-Hill. N.Y., 35 1963. pp. 8-59ff. 127 234 84 1 128 For further information regarding the art of formulation, see for example: H. M. Loux. U.S. Patent 3,235.361. Feb. 15. 1966. Col. 6. Line 16 through Col. 7, Line 19 and ^ 5 Examples 10 through 41.
R. W. Luckenbaugh. U.S. Patent 3.309.192.
March 14. 1967, Col. 5. Line 43 through Col. 7. Line 62 and Examples 8. 12. 15, 39. 41, 52, 53, 58. 132, 138-140, 162-164, 166, 167, 169-182. 10 H. Gysin and E. KnuBli, U.S. Patent 2.891,855, June 23. 1959. Col. 3. Line 66 through Col. 5. Line 17 and Examples 1-4.
G. C. Klingman, "Weed Control as a Science".
John Wiley and Sons. Inc.. New York. 1961. pp. 81-96. 15 J. D. Fryer and S. A. Evan6. "Weed Control Hand book". 5th Edn. Blackwell Scientific Publications. Oxford. 1968. pp. 101-103.
Examples of useful formulations of compounds of the formula I are as follows.
Wettable Powder 2-(2.4-difluorophenyl)-3- (4-fluorophenyl)-l-(1H-1.2,4-triazol-l-yl)-3-buten-l-ol; and the (S) enantiomer thereof 80* sodium alkylnaphthalenesulfonate 2* sodium ligninsulfonate 2* synthetic amorphous silica 3* kaolinite 13* The ingredients are blended, hammer-milled, re-blended and packaged.
Granule wettable powder of above example 15* gypsum 69* potassium sulfate 16* The ingredients are blended in a rotating or 35 fluid bed mixer and water sprayed on to accomplish granulation. When most of the material has reached 128 234841 129 the desired range of 1.0 to 0.42 ram. (U.S.S. No. 18 to 40 sieves), the granules are removed, dried, and screened. Oversize material is crushed to produce additional material in the desired range.
High Strength Concentrate 2-(2-fluorophenyl)-3-(4-fluorophenyl)-l-(lH-l.2.4-triazol-l-yl)-3-buten-2-ol; and the (S) enantiomer thereof 98.5% silica aerogel 0.5% synthetic amorphous fine silica 1.0% The ingredients are blended and ground in a hammer-mill to produce a high strength concentrate essentially all passing a U.S.S. No. 50 sieve (0.3 mm openings). This material may then be formulated in a variety of ways.
Aqueous Suspension 2-(2.4-difluorophenyl)-3-phenyl-1-(1H-1.2.4-triazol-l-yl)-3-buten-2-ol; and the (S) enantiomer thereof 25% hydrated attapulgite 3% crude calcium ligninsulfonate 10% sodium dihydrogen phosphate 0.5% water 61.5% The ingredients are ground together in a ball, sand, or roller mill until the solid particles have been reduced to diameters under 10 microns.
Solution 2-(2.4-difluorophenyl)-3-(4-chlorophenyl)-l-(1H-1.2.4-triazol-l-yl)-3-buten-2-ol; and the (S) enantiomer thereof 30% dimethylformamide 70% The ingredients are combined and stirred to produce a solution, which can be used for low volume applications. 129 234 84 1 130 Eraulsifiable Concentrate 2-(2,4-difluorophenyl)-3-(4-fluorophenyl)-l-(lH-1,2.4-triazol-l-yl)-3-buten-2-ol: and the (S) enantiomer thereof 15* blend of calcium sulfonates and nonionic surfactants 25* xylene 60* The ingredients are corabined and stirred until the active is dissolved. A fine screen filter is in-10 eluded in packaging operation to insure the absence of any extraneous undissolved material in the product. 130 234 84 1 O 131 Utility The compounds of formula I are useful as plant disease control agents. They are effective in controlling a broad spectrum of plant diseases, 5 particularly foliar pathogens of ornamental, vegetable, field, cereal and fruit crops, such as. Pucclnla. recondlta, Eryslphe clchorace&rum, Eryslphe gramlnls, Venturis, ln&equ&lis, Cetcospora. arachldlcola, and Monlllnla frucclcola, RhlzoctonlA sol&nl, Pyrlcularla oryz&e, Botrytls 10 clnerea, Pseudocercosporella herpotrichlorldes, and Cercosporldlum personatum. They also control seed pathogens.
Disease control is ordinarily accomplished by applying an effective amount of the compound 15 either pre- or post-infection to the portion of the plant to be protected, such as the roots, 6tems. foliage, fruit, seeds, tubers or bulbs, or to the media (soil or sand) in which the plants to be protected are growing. The compound may also be 20 applied to the seed from which the plants to be protected are to be grown.
Rates of application for these compounds can be influenced by many factors of the environment and should be determined under actual use conditions. 25 Foliage can normally be protected when treated at a rate of from less than 1 g/ha to 5000 g/ha of active ingredient. Plants growing in soil treated at a concentration from 0.1 to about 20 kg/ha can be |||^ protected from disease. Seed and seedlings can normally be protected when seed is treated at a rate of from 0.06 to about 3 grams per kilogram of seed.
The compounds of ;;£ormula I can be mixed with fungicides, bactericides, acaricides, nematicides. insecticides, or other biologically 35 active compounds in order to achieve desired results 131 ! 234841 O 132 | with a minimum expenditure of time, effort and j material. Amounts of these biologically active ] materials added for each part by weight of the j composition of this invention may vary from 0.05 to j 5 25 parts by weight. Suitable agents of this type are f j well-known to those skilled in the art. Some are listed below: Fungicides methyl 2-benzimidazolecarbamate (carbendazim) ■ tetramethylthiuram disulfide (thiuram) | n-dodecylguanidine acetate (dodine) manganese ethylenebisdithiocarbamate (maneb) 1.4-dichloro-2. 5-dimethoxybenzene (chloroneb)methyl 15 l-(butylcarbamoyl)-2-benzimidazolecarbamate (benomyl) 2-cyano-N-ethylcarbamoyl-2-methoxyiminoacetamide (cymoxanil) N-trichloromethylthiotetrahydrophthalaraide (captan) N-trichloromethylthiophthalimide (folpet) dimethyl 4.4'-(o-phenylene)bis(3-thioallophanate)-(thiophanate-methyl) 2-(thiazol-4-yl)benzimidazole (thiabendazole) aluminum tris(0-ethyl phosphonate)(phosethyl aluminum) tetrachloroisophthalonitrile (chlorothalonil) 2.6-dichloro-4-nitroaniline (dichloran) N-(2.6-dimethylphenyl)-N-(methoxyacetyl)alanine methyl ester (metalaxyl) cis-N-[1.1.2.2-tetrachloroethyl)thio]cyclohex-4-ene-1.2-dicarbioxiraide (captafol) 30 3-(3.5-dichlorophenyl)-N-(1-raethylethyl)-2.4-dioxo-l-imidazolidine carboxamide (iprodione) 3-(3.5-dichlorophenyl)-5-ethenyl-5-raethyl-2.4-oxazoli-dinedione (vinclozolin) kasugamycin O-ethyl-S.S-diphenylphosphorodithioate(edifenphos) 4-(3-(4-(1.l-dimethyl-ethyl)phenyl)-2-methyl)propyl-2.6-dimethylmorpholine (Fenpropimorph) 132 ~"v;' . 23 4 133 Bactec icides tribasic copper sulfate streptomycin sulfate oxytetracycline Acaricides senecioic acid, ester with 2-sec-butyl-4.6-dinitro- phenol (binapacryl) 6-methyl-l.3-dithiolo[2,3-B]quinonolin-2-one (oxythio-10 quinox) 2.2.2-trichloro-l.1-bis(4-chlorophenylJethanol-(dicofol) bis(pentachloro-2.4-cyclopentadien-l-yl)(dienochlor) tricyclohexyltin hydroxide (cyhexatin) 15 hexakis(2-methyl-2-phenylpropyl)distannoxane (fenbutin oxide) Nematicides 2-[diethoxyphosphinylimino]-l,3-diethietane 20 (fosthietan) S-methy1-1-(dimethylcarbamoyl)-N-(methylcarbamoyloxy)- thioformimidate(oxamyl) S-methyl-l-carbamoyl-N-(methylcarbamoyloxy)thio-formimidate N-isopropylphosphoramidic acid. 0-ethyl-0'-[4-(methyl-thio)-m-tolyl]diester (fenamiphos) Insecticides 3-hydroxy-N-methyIcrotonamide(dimethyIphosphate)ester 30 (monocrotophos) methylcarbamic acid, ester with 2.3-dihydro-2.2- diraethyl-7-benzofuranol (carbofuran) O—[2.4.5-trichloro-a-(chloromethyl)benzyl]phosphoric acid. O'.O'-diraethyl ester (tetrachlorvinphos) 133 2343 134 2-raercaptosuccinic acid, diethyl ester. S-ester with thionophosphoric acid, dimethyl ester (raalathion) phosphorothioic acid, O,O-dimethyl. 0-£-nitrophenyl ester (methyl parathion) methylcarbamic acid, ester with a-naphthol (carbaryl) methyl N-[[(methylamino)carbonyl]oxy]ethanimidothio- ate (raethomyl) N' -(4-chlor o-o.-to lyl) -N.N-dimethylf ormamidine 10 (chlordimeform) 0.0-diethyl-0-(2-isopropyl-4-methyl-6-pyrimidyl)- phosphorothioate (diazinon) octachlorocamphene (toxaphene) O-ethyl O-jj-nitrophenyl phenylphosphonothioate (EPN) 15 cyano(3-phenoxyphenyl)-methyl 4-chloro-a-(l-methyl-ethyl)benzeneacetate (fenvalerate) (3-phenoxyphenyl)methyl (+)-cis.trans-3-(2.2-dichloro-ethenyl)-2,2-dimethylcyclopropanecarboxylate (permethrin) dimethyl N.N'-[thiobis(N-methylimmo)carbonyloxy]]-bis[ethanimidothioate] (thiodicarb) phosphotothiolothionic acid, O-ethyl-O-t4-(methyl- thio)phenyl]-S-n-propyl ester (sulprofos) a-cyano-3-phenoxybenzyl 3-(2,2-dichlorovinyl)-2.2-5 dimethylcyclopropane carboxylate (cypermethrin) cyano(3-phenoxyphenyl)methyl 4-(difluoromethoxy)- a-(methylethyl)benzeneacetate (flucythrinate) O.O-diethy1-0-(3,5.6-trichloro-2-pyridyl)phosphoro-thioate (chlorpyrifos) 0 0,0-dimethyl-S-[(4-oxo-l,2,3-benzotriazin-3-(4H)-yl)-raethyl]phosphorodithioate (azinphos-methyl) 5.6-dimethyl-2-dimethylamino-4-pyrimidinyl dimethyl carbamate (pirimicarb) S-(N-formyl-N-methylcarbamoylmethyl)-0.O-dimethyl 5 phosphorodithioate (formothion) 134 2 3 4 O r-i 135 S-2-(ethylthioethyl)-0.O-dimethyl phosphiorothioate (demeton-S-methyl) a-cyano-3-phenoxybenzyl cis-3-(2.2-dibcomovinyl)- 2.2-dimethylcyclopropane carboxylate (deltaroethrin) cyano(3-phenoxyphenyl)methyl ester of N-(2-chloro-4-trifluoromethylphenyl)alanine (fluvalinate) This invention is further illustrated by the following examples. 135 234 136 Example A The test compounds were dissolved in acetone in an amount equal to 6* of the final volume and then suspended at a concentration of 100 or 20 ppra in purified water containing 250 ppra of the surfactant TREM 014 (polyhydric alcohol esters). This suspension was sprayed to the point of run-off on apple seedings. The following day plants were inoculated with a spore suspension of Venturia inaequalis. the causal agent of apple scab, and incubated in a saturated humidity chamber at 20°C for 24 hours and then in a growth chamber at 22°C for 11 days, when disease ratings were made.
Example B The test compounds were dissolved in acetone in an amount equal to 6* of the final volume and then suspended at a concentration of 100 or 20 ppm in purified water containing 250 ppm of the surfactant TREM 014 (polyhydric alcohol esters). This suspension was sprayed to the point of run-off on peanut seedlings. The following day plants were inoculated with a spore suspension of Cercosporidium personatura. the causal agent of Peanut Late Leafspot. and incubated in a saturated humidity chamber at 22°C for 24 hours, then in a high humidity chamber at 27°C for 7 days, and then in a growth chamber at 29°C for 7 days, when disease ratings were made.
Example C The test compounds were dissolved in acetone in an amount equal to 6\ of the final volume and then suspended at a concentration of 100 or 20 ppm in purified water containing 250 ppm of the surfactant TREM 014 (polyhydric alcohol esters). This 136 23484 137 suspension was sprayed to the point of run-off on broad bean seedlings. The following day plants were inoculated with a spore suspension of Botrvtis cinerea. the causal agent of bean grey mold, and 5 incubated in a saturated humidity chamber at 20°C for 24 hours when disease ratings were made.
Example D The test compounds were dissolved in acetone 10 in an amount equal to 6* of the final volume and then suspended at a concentration of 100 or 20 ppm in purified water containing 250 ppra of the surfactant TREM 014 (polyhydric alcohol esters). This suspension was sprayed to the point of run-off on wheat seedlings. The following day plants were inoculated with a spore dust of Ervsiohe qraminis f. sp. tritici. the causal agent of wheat powdery mildew, and incubated in a growth chamber at 20°C for 6 days, when disease ratings were made.
Example E The test compounds were dissolved in acetone * in an amount equal to 6* of the final volume and then suspended at a concentration of 100 or 20 ppm in purified water containing 250 ppm of the surfactant TREM 014 (polyhydric alcohol esters). This suspension was sprayed to the point of run-off on rice seedlings. The following day plants were inoculated with a spore suspension of Pvricularia orvzae. the causal agent of rice blast, and incubated in a saturated humidity chamber at 27°C for 24 hours and then in a growth chamber at 29°C for 4 days, when disease ratings were made. 137 138 Example F The test compounds were dissolved in acetone in an amount equal to 6* of the final volume and then suspended at a concentration of 100 or 20 ppm in 5 purified water containing 250 ppra of the surfactant TREM 014 (polyhydric alcohol esters). Thi6 suspension was sprayed to the point of run-off on rice seedlings. The following day plants were inoculated with a spore suspension of Rhizoctonia 10 solani. the causal agent of rice sheath blight, and incubated in a saturated humidity chamber at 27°C for 48 hours and then in a growth chamber at 29°C for 4 days, when disease ratings were made.
Example G The test compounds were dissolved in acetone in an amount equal to 61 of the final volume and then suspended at a concentration of 100 or 20 ppm in purified water containing 250 ppm of the surfactant TREM 014 (polyhydric alcohol esters). This suspension was sprayed to the point of run-off on wheat seedlings. The following day plants were inoculated with a spore suspension of Puccinia recondita. the causal agent of wheat leaf rust, and incubated in a saturated humidity chamber at 20°C for 24 hours and then in a growth chamber at 20°C for 8 days, when disease ratings were made.
Example H The test compounds were dissolved in acetone in an amount equal to 6* of the final volume and then suspended at a concentration of 100 or 20 ppra in purified water containing 250 ppra of the surfactant TREM 014 (polyhydric alcohol esters). This suspension was sprayed to the point of run-off on 138 V r* "v" «w v_ 234 84 1 139 tomato seedlings. The following day plants were inoculated with a spore suspension of Phvtophthora infestans. the causal agent of tomato late blight, and incubated in a saturated humidity chamber at 20°C ) 5 for 24 hours and then in a growth chamber at 20°C for days, when disease ratings were made.
Example I The test compounds were dissolved in acetone G 10 in an amount equal to 6\ of the final volume and then suspended at a concentration of 100 or 20 ppm in purified water containing 250 ppm of the surfactant TREM 014 (polyhydric alcohol esters). This suspension was sprayed to the point of run-off on 15 grape seedlings. The following day plants were inoculated with a spore suspension of Plasmorpara viticola. the causal agent of grade downy mildew, and incubated in a saturated humidity chamber at 20°C for 24 hours, then in a growth chamber at 20°C for 7 days 20 and then held in a saturated humidity chamber at 20°C for 24 hours, when disease ratings were made.
Example J The test compounds were dissolved in acetone 25 so that 1 ml of solution yielded a concentration of 0.5 kilogram/hectare when added to cucumber seeds and soil in pots. Seeds and soil were then inoculated with a mixture of sand, cereal and mycelium of the fungus Pvthium a p ha na derma turn, causal agent of 30 cucumber damping off. and incubated in a growth chamber at 30°C for 14 days. Disease ratings were then made.
Example K The test compounds were dissolved in acetone so that 1 ml of solution yielded a concentration of 1 1 13 9 '""v, • . v '' -i - ' 23484t o *4p»* 140 0.5 kilogram/hectare when added to cotton seeds and soil in pots. Seeds and soil were then inoculated with a mixture of sand, cereal and mycelium of the fungus Rhizoctonia solani. causal agent of cotton 5 blight, and incubated in a growth chamber at 30°C for 14 days. Disease ratings were then made.
Example L The test compounds were dissolved in acetone 10 so that 1 ml of solution yielded a concentration of 0.5 kilogram/hectare when added to cucumber seeds and soil in pots. Seeds and soil were then inoculated with a mixture of sand, cereal and mycelium of the fungus Fusarium oxysporum f. sp. cucumerinum. causal 15 agent of cucumber wilt, and incubated in a growth chamber at 30°C for 14 days. Disease ratings were then made.
Example M The test compounds were dissolved in acetone so that 1 ml of solution yielded a concentration of 0.5 kilogram/hectare when added to lima bean seeds and soil in pots. Seeds and soil were then inoculated with a mixture of sand, cereal and 25 mycelium of the fungus Sclerotium rolfsii. causal agent of southern blight, and incubated in a growth chamber at 30°C for 14 days. Disease ratings were then made.
Results for Examples A-M are given in Table 7. In this table, a rating of 100 indicates 100* disease control and a rating of 0 indicates no disease control relative to the controls. A - entry indicates that no test was performed with the 35 specified compound. A P entry indicates that disease control was not measured due to phytoxicity. 140 " ■ ■ ' •* fS 234 84 1 141 -V Table 7 ".t 1 J Ex.
Rate Ex. Ex.
Ex.
Ex.
Ex.
Ex. Ex.
Ex.
Ex.
Rate Ex.
Ex.
Ex.
Ex. 4 -'* 1 Wo.
(PPM) A B C D E _F G_ H 1 (ks/ha) J K L M { 1 100 62 100 81 98 90 97 100 0 12 0 P 0 P I G 2 100 62 100 93 98 95 100 100 0 99 0 P 0 P 3 100 100 100 93 93 93 100 0 0 0 0 P P Q 4 100 100 100 88 100 96 100 100 0 81 0 0 P 0 6 100 0 82 84 98 0 0 96 23 0 0 0 P 0 100 0 76 52 63 0 17 64 0 0 0 0 0 0 s C 100 100 100 99 100 1 93 100 26 0 0 p 0 P Cr 16 100 0 0 0 23 0 0 P 0 s 1 74 99 27 67 0 0 100 - - 3 17 100 0 81 0 42 0 0 P 0 80 100 57 95 0 0 100 - - £' 100 100 100 96 91 31 48 97 0 0 0 p P 26 100 100 100 96 86 31 61 97 23 86 0 27 100 62 100 88 98 95 100 100 24 84 0 0 0 0 ? 28 100 89 100 88 98 81 100 100 0 6 0 0 0 0 A 32 100 100 100 98 95 97 33 100 0 98 0 0 P P - 33 100 20 47 99 56 37 89 0 0 60 29 100 0 24 0 0 0 0 !- 34 100 69 100 94 60 86 16 66 0 0 0 0 0 0 100 100 100 96 100 0 100 96 0 26 0 0 0 0 -- HI 39 100 89 97 96 98 7 100 100 0 81 0 0 0 0 40 100 19 100 80 91 7 61 96 0 0 0 0 0 0 41 100 100 100 96 98 7 97 100 0 100 0 0 0 0 42 100 20 29 100 100 38 100 98 31 15 41 0 100 0 23 — — — — 0 47 100 31 47 0 - - - - 93 100 26 98 0 100 - - 49 100 89 100 62 100 76 96 100 0 0 0 P 0 P 50 100 100 100 98 95 86 93 100 0 46 0 P 0 P 51 100 100 100 96 100 0 100 100 0 0 p P p P 52 100 100 100 95 94 93 81 100 0 0 0 P 0 0 141 %rvv4tw'^^-• ?a v--' 234 84 1 142 Table 7 (Continued) Ex.
Rate Ex.
Ex.
Ex.
Ex.
Ex.
Ex.
EX.
Ex.
Ex.
Rate Ex.
Ex.
Ex.
Ex.
No.
(PPM) A B C D E *F G H I (kK/ha) J K L H 65 100 34 96 94 85 62 100 0 0 0 0 0 0 67 100 - 0 68 - 2 1 0 0 0 0 58 99 60 85 0 89 - - 94 100 86 61 96 98 78 36 100 0 0 0 0 p p 99 100 100 100 89 83 98 61 100 0 83 0 0 p p 100 100 100 100 96 83 95 80 100 0 83 P 0 p 0 101 100 100 100 94 83 0 80 100 0 100 0 0 p 0 163 100 - 0 - 0 0 - - - - 0 81 58 23 0 99 - - 164 100 - 0 - 8 0 - - - - 82 100 57 88 0 100 - - 170 100 - - 0 0 - - - - 19 69 32 95 0 0 100 - - 177 100 - 0 - 0 0 - - - - 82 26 50 46 0 0 100 - - 208 100 84 37 83 76 4 61 97 0 74 0 0 0 0 291 100 - 1 0 - 24 78 - - - - 32 26 6 83 1 0 73 - - - 359 100 72 100 83 95 88 62 100 0 0 0 0 0 0 360 100 88 100 71 86 74 49 93 0 0 0 0 0 0 361 100 - 1 0 - 27 9 - - - - 43 26 29 33 1 0 100 - - 363 100 0 49 92 28 0 0 38 0 0 0 0 0 0 447 100 - 0 24 46 46 0 0 24 0 0 0 0 448 100 - 0 54 - 0 42 16 0 0 - - - - 449 100 71 0 24 0 76 13 0 51 0 0 0 0 450 _ 100 - 0 54 11 46 34 0 51 0 0 0 0 451 100 16 100 72 0 0 0 0 0 0 0 0 0 0 452 100 36 0 54 46 0 67 0 0 0 0 0 0 453 100 55 32 75 94 0 0 100 0 0 0 0 0 0 142 143 Table 7 (Continued) 23 4 8 4 t Ex.
Rate Ex. Ex.
Ex.
EX.
Ex.
Ex. Ex.
Ex.
Ex.
Rate Ex.
Ex.
Ex.
Ex.
No.
(PPM) A B C D E _F G_ H I (kR/ha) J K L M 454 100 0 0 0 22 0 0 0 0 0 - - - - 455 100 64 65 0 12 0 0 43 0 0 0 0 0 0 456 100 82 0 58 53 98 0 96 9 0 0 0 0 0 477 100 95 100 76 100 48 48 100 0 0 P p P p 594 100 86 100 93 77 2 - 100 0 79 0 60 100 50 596 100 0 0 0 - - - - 91 95 94 0 0 100 - - 603 100 44 97 91 69 0 - 95 0 0 0 0 0 0 605 100 70 99 32 81 0 - 100 0 0 0 0 0 0 608 100 87 100 98 98 4 81 100 0 0 0 0 p p 618 100 100 100 98 89 0 - 100 0 0 0 80 80 p 620 100 100 100 96 98 51 100 100 0 0 0 0 P 0 622 100 100 100 84 99 0 100 100 0 26 0 0 P 0 627 100 0 14 0 61 - - - - 31 70 19 81 0 0 99 - - 644 100 100 100 94 100 100 100 100 23 0 0 0 P p 646 100 100 100 95 98 97 61 100 0 99 100 0 0 0 651 100 0 62 0 .46 0 0 o 0 67 0 7 67 0 0 100 - - 656 100 93 100 88 97 0 50 100 0 0 p p p 657 100 62 100 81 98 49 97 100 24 37 0 0 0 0 661 100 0 70 85 - - - - 81 79 61 62 0 100 - - 663 100 42 100 95 99 57 36 100 0 39 - - - - 667 100 0 0 0 0 0 0 0 13 14 7 39 0 0 0 - - 668 100 1 0 22 31 - - - - 65 17 31 31 1 0 100 - - 669 100 100 100 90 : 100 96 : 100 100 0 0 0 0 p 0 671 100 100 100 92 94 84 : 100 100 0 84 0 p p 0 143 .•-is •■tfV.'r - 7-y"; »»*-.■< w »sws(?¥r'?^s?': -'• ':''''•'1'" \.. \ 1 O 23 4 84 1 144 Table 7 (Continued) Ex.
Rate Ex. Ex.
Ex.
EX.
Ex.
Ex. Ex.
Ex.
Ex.
Rate Ex.
Ex.
Ex.
Ex.
Mo.
(PPM) 1 A B C D . E _F G_ H I J -JL L 6 75 100 - - 0 62 0 69 - — _ 40 0 42 44 0 0 16 - - 685 100 0 29 - - - - - — 57 66 28 67 - 721 100 73 89 95 94 18 100 100 0 0 P p P P 724 100 100 100 95 100 63 100 100 0 0 0 p P . P 726 100 - - - 0 0 0 38 0 0 0 75 0 23 81 0 0 100 - - 815 100 40 98 0 62 2 - 97 0 65 0 0 0 0 90S 100 0 37 0 87 0 0 0 0 7 0 47 0 0 16 - - 1276 100 100 96 100 1 97 100 0 0 0 p 0 p 93 100 86 100 1 52 100 - - 1276a 100 1 0 16 22 - - - - 42 26 33 88 1 0 100 - - 1277 100 9 65 0 0 0 0 39 0 0 0 0 0 1277a 100 1 52 - 8 31 - - - - 58 74 24 95 1 0 100 - - - 1278 100 100 100 87 85 17 36 100 0 16 0 0 0 0 1300 100 100 100 93 92 58 81 100 0 0 0 0 0 0 1304 100 100 100 97 100 78 88 100 0 18 0 0 0 0 1377 100 100 100 96 92 58 : 100 100 0 44 0 p 0 p 1381 100 100 100 97 98 51 73 100 0 78 0 50 0 0 1451 100 86 84 48 77 2 - 93 0 79 0 0 0 0 1459 100 72 70 65 31 17 0 65 0 74 0 0 0 0 1468 100 40 0 0 77 2 - 93 0 46 0 60 0 0 1469 100 68 84 81 77 2 - 100 24 89 0 80 70 0 1527 100 0 100 93 100 — 100 0 0 0 P 0 p 14 4 >*r .*&&}■'i J'.ti- ■s"- v- ". 'y* .■■>."• ■ ' '• ""■*" V'.'""1 • ' tr

Claims (7)

WHAT WE CLAIM IS;
1. A compound of the formula: crr1o « /\r3R4 <IX) atch2}nc"?— b o 234 84 1 in which A is perfluoroalkyl of 1-8 carbon atoms, N(CH3)2# OH. naphthyl optionally substituted with a total of 1-3 substituentB each of which is independently selected from halogen and CF3# optionally substituted with 1 or 2 methyl groups, phenyl optionally substituted with a total of 1-3 substituents each of which is independently selected from: halogen, alkyl of 1-4 carbon atoms, haloalkyl of 1-4 carbon atoms, alkoxy of 1-4 carbon atoms, and with no more than one group selected from: haloalkoacy of 1-4 carbon atoms, S(O) R5. R6, 2-.3-.or 4-m pyridyl. imidazol-l-yl. 1.2.4- tr iazol-l-yl, and -l^ X optionally substituted with 1 or 2 methyl groups. or a heterocycle selected from imidazol-l-yl, 1,2.4-triazol-l-yl, 2-or 3-thienyl. and 2-.3-,or 4-pyridyl optionally substituted with one or two substituents each of which is independently selected from: halogen, alkyl of 1-4 carbon atoms, CF,. and S(O) R5; 3 m B is alkyl of 1-8 carbon atoms, naphthyl, biphenyl, CH. X perfluoroalkyl of 1-8 carbon atoms. - 146 - 234841 phenyl optionally substituted with 1-3 substituents each of which is independently selected from: halogen, alkyl of 1-4 carbon atoms, haloalkyl of 1-4 carbon atoms, alkoxy of 1-4 carbon atoms, and with no more than one group selected from haloalkoxy of 1-4 5 carbon atoms, or S(O) R . m benzyl optionally substituted on the phenyl ring with halogen or alkyl of 1-4 carbon atoms, or optionally a-substituted with 1 or 2 methyl groups, or a heterocycle selected from 2-or 3-thienyl. and 2-.3-.or 4-pyridyl optionally substituted with one or two substituents each of which is independently selected from: halogen, alkyl of 1-4 carSon atoms. CF3 or S(0)mR5; / v n is 0 to 4 with the proviso that when A is -N^ X, N(CH3)2, or OH, then n is other than 0; m at each occurrence is 0, 1 or 2; X is C, NR10, or 0; R and R1 independently are H. alkyl of 1-4 carbon atoms, halogen, or phenyl, or taken together form cycloalkyl of 3-7 carbon atoms; 3 4 R and R independently are H. F. or alkyl of 1-4 carbon atoms; R5 is alkyl of 1-4 carbon atoms; R is phenyl optionally substituted with a total of 1-3 substituents each of which is independently selected from halogen and CF3; with the provisos that (i) a and b are not both phenyl when R, R , R and R4 are hydrogen and n=0; and (ii) that R and R4 are not both F or not b^Lth alkyl. A compound of the formula: CRR1 OH u A(CH-) C. C_ PR3D4
2 n , R (Ila) B T ■*$ - 147 - 234841 wherein A, B, R, R1, R3, R4, and n are as defined in claim 1 (but excluding the proviso that A and B are not both phenyl when R, R1, R3, R4 are H and n=0), and T is Br, Cl or I, with the proviso that R3 and R4 are not both F or not both alkyl.
3. A process for preparing a compound of claim 1 or 2 which comprises: contacting in an inert solvent: a compound of the formula: CRR1 A(CH2)nCM where M is MgX or Li. and X is Cl, Bf or I. with a haloketone of the formula: o B-C-C-X r r where X is Br or Cl and A. B. R. R1. R3. R4 and n are as defined in claim 1 (but excluding the proviso that A and B are not both phenyl when R, R1, R3, R4 are H and n=0).
4. A process for preparing a compound of claim 2 which comprises: contacting in an inert solvent: a compound of the formula: 0 °v " / \ 3 4 a(ch ) c-c cr r 2 n , B with a compound of the formula: (c6h5)3p=crr1 13 4 where A. B. R. R . R , R and n are as defined in claim 1 (but excluding the proviso 13 4 that A and B are not both phenyl when R, R , R , R are H and n=0).
5. A compound as claimed in claim 1 or claim 2 and as specifically identified in this^specification. - 148 -
6. A process for producing a compound as claimed in claim 1 or claim 2 substantially as described in this specification.
7. A compound of formula II or Ila whenever prepared by a process according to any one of claims 3, 4 and 6. E„I. DU PONT DE NEMOURS AND COMPANY
NZ23484187A 1986-06-23 1987-06-22 Intermediates for preparing antifungal carbinols NZ234841A (en)

Applications Claiming Priority (3)

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US87752586A 1986-06-23 1986-06-23
US4254187A 1987-04-29 1987-04-29
NZ220798A NZ220798A (en) 1986-06-23 1987-06-22 1,2,4-triazoles and fungicidal compositions

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NZ234841A true NZ234841A (en) 1990-11-27

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