AP803A - Bicyclic amines. - Google Patents

Bicyclic amines. Download PDF

Info

Publication number
AP803A
AP803A APAP/P/1997/001139A AP9701139A AP803A AP 803 A AP803 A AP 803A AP 9701139 A AP9701139 A AP 9701139A AP 803 A AP803 A AP 803A
Authority
AP
ARIPO
Prior art keywords
cyano
chloropyrid
mixture
exo
endo
Prior art date
Application number
APAP/P/1997/001139A
Inventor
Christopher Richard Ayles Godfrey
Christopher John Urch
Martin Stephen Clough
Roger Salmon
Terence Lewis
Original Assignee
Zeneca Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Zeneca Ltd filed Critical Zeneca Ltd
Application granted granted Critical
Publication of AP803A publication Critical patent/AP803A/en

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D451/00—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof
    • C07D451/02—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
    • A01N43/34—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one nitrogen atom as the only ring hetero atom
    • A01N43/40—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one nitrogen atom as the only ring hetero atom six-membered rings
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
    • A01N43/90—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having two or more relevant hetero rings, condensed among themselves or with a common carbocyclic ring system
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N47/00—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom not being member of a ring and having no bond to a carbon or hydrogen atom, e.g. derivatives of carbonic acid
    • A01N47/08—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom not being member of a ring and having no bond to a carbon or hydrogen atom, e.g. derivatives of carbonic acid the carbon atom having one or more single bonds to nitrogen atoms
    • A01N47/10—Carbamic acid derivatives, i.e. containing the group —O—CO—N<; Thio analogues thereof
    • A01N47/16—Carbamic acid derivatives, i.e. containing the group —O—CO—N<; Thio analogues thereof the nitrogen atom being part of a heterocyclic ring
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N47/00—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom not being member of a ring and having no bond to a carbon or hydrogen atom, e.g. derivatives of carbonic acid
    • A01N47/08—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom not being member of a ring and having no bond to a carbon or hydrogen atom, e.g. derivatives of carbonic acid the carbon atom having one or more single bonds to nitrogen atoms
    • A01N47/10—Carbamic acid derivatives, i.e. containing the group —O—CO—N<; Thio analogues thereof
    • A01N47/22—O-Aryl or S-Aryl esters thereof
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N47/00—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom not being member of a ring and having no bond to a carbon or hydrogen atom, e.g. derivatives of carbonic acid
    • A01N47/08—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom not being member of a ring and having no bond to a carbon or hydrogen atom, e.g. derivatives of carbonic acid the carbon atom having one or more single bonds to nitrogen atoms
    • A01N47/28—Ureas or thioureas containing the groups >N—CO—N< or >N—CS—N<
    • A01N47/38—Ureas or thioureas containing the groups >N—CO—N< or >N—CS—N< containing the group >N—CO—N< where at least one nitrogen atom is part of a heterocyclic ring; Thio analogues thereof
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond

Landscapes

  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Dentistry (AREA)
  • Wood Science & Technology (AREA)
  • Plant Pathology (AREA)
  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Agronomy & Crop Science (AREA)
  • General Health & Medical Sciences (AREA)
  • Pest Control & Pesticides (AREA)
  • Zoology (AREA)
  • Environmental Sciences (AREA)
  • Pyridine Compounds (AREA)
  • Agricultural Chemicals And Associated Chemicals (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

A compound of formula (I), wherein R1 represents a group of formula (A) where each of W, X, Y and Z represents either a grou CR or the nitrogen atom, provided that not more than two of W, X, Y and Z represent the nitrogen atom and where each R present i independently selected from hydrogen and halogen atoms and cyano, amino, hydrazino, acylamino, hydroxy, alkyl, hydroxyalkyl, alkox) haloalkyl, haloalkoxy, alkenyl, alkcnyloxy, alkoxyalkenyl, alkynyl, carboxylic acyl, alkoxycarbonyl, aryl and hetcrocyclyl groups, sai groups comprising up to 6 carbon atoms, and wherein R2 represents hydrogen or cyano or a group selected from alkyl, aryl, heteroary aralkyl, heteroarylalkyl, alkenyl, aralkenyl, alkynyl, alkoxycarbonyl, alkanesulfonyl, arenesulfonyl, alkanyloxycarbonyl, aralkyloxycarbony aryloxycarbonyl, hetcrocyclyalkyl, carbamyl or dithiocarboxyl groups, said groups comprising from 1 to 15 carbon atoms, said groups bein optionally substituted with one or more substituents selected from, halogen, cyano carboxyl, carboxylic acyl, carbamyl, alkoxycarbony alkoxy, alkylcnedioxy, hydroxy, nitro, haloalkyl, alkyl, amino, acylamino, imidate and phosphonato groups; and acid addition salts an quaternary ammonium salts and N-oxidc derived therefrom. The compounds are useful as insecticides.

Description

BICYCLIC AMINES AS INSECTICIDES
This invention relates to novel bicyclic amines, to processes for preparing them, to insecticidal compositions comprising and to methods of combatting and controlling insect pests therewith.
The invention provides compounds of formula (I) wherein R1 represents a group of formula (A) where each of W, X, Y and Z and Z represents either a group CR or the nitrogen atom, provided that not more than two of W, X, Y and Z represent the nitrogen atom and where each R present is independently selected from hydrogen and halogen atoms and cyano, amino, hydrazino, acylamino, hydroxy, alkyl, hydroxyalkyl, alkoxy, haloalkyl, haloalkoxy, alkenyl, alkenyloxy, alkoxyalkenyl, alkynyl, carboxylic acyl, alkoxycarbonyl, aryl and heterocyclyl groups, said groups comprising up to 6 carbon atoms, and wherein R2 represents hydrogen or cyano or a group selected from alkyl, aryl, heteroaryl, aralkyl, heteroarylalkyl, alkenyl, aralkenyl, alkynyl, alkoxycarbonyl, alkanesulfonyl, arenesulfonyl, alkanyloxycaibonyl, aralkyloxycarbonyl, aryloxycarbonyl, heterocyclylalkyl, carbamyl or dithiocarboxyl groups, said groups comprising from 1 to 15 carbon atoms, said groups being optionally substituted with one or more substituents selected from, halogen, cyano, carboxyl, carboxylic acyl, carbamyl, alkoxycarbonyl, alkoxy, alkylenedioxy, hydroxy, nitro, haloalkyl, alkyl, amino, acylamino, imidate and phosphonato groups; and acid addition salts and quaternary ammonium salts and N-oxides derived therefrom. R1 is preferably a halo.... 20 substituted phenyl, pyridyl or diazinyl group.
' In a preferred aspect invention provides compounds of formula (I) where R1 represents an optionally halogen substituted phenyl group or an optionally halogen substituted pyridyl, pyridazinyl or pyrazinyl.group and R2 represents hydrogen or a alkyl, alkenyl, alkynyl, phenyl, benzyl, pyridylmethyl, thienylmethyl, thiazolylmethyl group which may be optionally substituted with one or more alkyl, alkoxy, alkoxycarbonyl, cyano, optionally substituted alkane sulphonyl groups or halogen atoms; and acid addition salts thereof.
One particularly preferred group of compounds are those wherein R1 represents an optionally halogen substituted phenyl or pyridyl group and R2 represents a alkyl group containing up to 4 carbon atoms which may optionally be substituted with one or more halogen atoms.
AP/P/ 97 / 0 1139
An especially preferred group of compounds are those wherein R1 represents a 5halopyrid-3-yl group and R2 represents hydrogen or a haloalkyl, haloalkenyl or halobenzyl group.
Specific compounds of formula I according to the invention include those set out in 5 Table I below in which the groups represented by R1 and R2 are given for each compound, together with the melting point (°C) or an indication of the physical state of the compound.
TABLE I
Compound No R1 R2 Melting Point
1 3,5-dichlorophenyl methyl 145-146 °C
2 3,5-difluoropheny 1 methyl 93-94 °C
3 2,3-difluorophenyl methyl oil
4 pentafluorophenyl methyl oil
5 2,3-dichlorophenyl methyl solid
6 4-methoxyphenyl benzyl (Isomer A) 178.4 °C
7 4-methoxyphenyl benzyl (Isomer B) 95-100 °C
8 phenyl benzyl 90-90.5 °C
9 3,5-difluorophenyl H 112.1 °C
10 3,5-difluorophenyl benzyl 85.2 °C
11 3,5-difluorophenyl 5,6-dichloropyrid-3- ylmethyl 143.2-144.2 °C
12 3,5-difluoropheny 1 pyrid-2-ylmethyl 127.9-128.5 °C
13 3,5-difluorophenyl 3-methylbenzyl 95.9-96.1 °C
14 3,5-difluorophenyl 4-chlorobenzyl 95.5-96.7 °C
15 3,5-difluorophenyl pyrid-3-ylmethyl 78.2 °C
16 3,5-difluorophenyl 3,4-methylenedioxybenzy 1 oil
17 3,5-difluorophenyl 3,5-dichlorobenzyl 154.1 °C
18 3,5-difluorophenyl 3,3-difluoroprop-2-en-1 -yl 94.6 °C
19 3,5-difluorophenyl 2-hydroxy-2-phenylethyl 120.8 °C
20 3,5-difluorophenyl 1-pheny 1-2-hydroxyethyl 168.8 °C
21 3,5-difluorophenyl allyl 70.5 °C
22 3,5-difluorophenyl propargyl 108.4 °C
23 3,5-difluorophenyl 2-fluoroethyl oil
24 3,5 -difluorophenyl 2-hydroxyethyl 100.4 °C
25 3,5-difluorophenyl 2-methoxyethyl 54.8 °C
26 3,5-difluorophenyl 2-cyanoethyl 115 °C
27 3,5-difluorophenyl 5-chlorothien-2-ylmethyl 114 °C
28 3,5-difluorophenyl 6-chloropyrid-2-yl gum
29 3,5-difluorophenyl 2-methylthiazol-5-ylmethyl 140 °C
30 3,5-difluorophenyl 2-iminyl-2-methoxyethyl 109 °C
31 phenyl benzyl (exo-isomer) 115-116 °C
32 phenyl benzyl (endo-isomer) 97 °C
33 pyrid-3-yl methyl 87 °C
AP.0 0 8 0 3
Compound No R1 R2 Melting Point
34 pyrid-3-yl 2-fluoroethyl 86-88 °C
35 pyrid-3-yl allyl 90-92 °C
36 pyrid-3-yl H 80-81 °C
37 pyrid-3-yl benzyl 119-120 °C
38 pyrid-3-yl ethyl oil
39 pyrid-3-yl t-butoxycarbonylmethyl gum
40 N-methylpyri.dinium-3-yl t-butoxycarbonyl (iodide) 185-187 °C
41 6-chloropyridazin-3-yl ' methyl 119-120 °C
42 pyrid-3-yl propyl oil
43 6-chloropyrazin-2-yl methyl 80 °C
44 pyrid-3-yl methane- sulphonylmethylsulphonyl 163-164 °C
45 pyrid-3-yl methane-sulphonyl 135 °C
46 6-chloropyrid-3-yl methyl gum
47 pyrid-3-yl methoxymethyl oil
48 pyrid-3-yl ethoxymethyl oil
49 pyrid-3-yl cy anomethyl 90-91 °C
50 pyrid-3-yl ethoxycarbonylmethyl gum
51 pyrid-3-yl methoxycaibonylmethyl gum
52 2-fluoro-4-nitrophenyl methyl 100-102 °C
53 3-fluorophenyl methyl oil
54 pyrid-3-yI 2-hydroxyethyl 155.2-156.8 °C
55 5,6-dichloropyrid-3-yl methyl 110.1-111.4 °C
56 pyrid-3-yl propargyl 119-8-121.1 °C
57 pyrid-3-yl methyl gum
58 pyrid-3-yl but-2-en-l-yl 193-194 °C
59 3,5-difluorophenyl 4-nitrophenyl 96.9-97.9 °C
60 5-chloropyrid-3-yl methyl 152.8-154.5 °C
61 pyrid-3-yl phenyl 136-137 °C
62 pyrazin-2-yl methyl 76-76.9 °C
63 2,6-dichloropyrimid-4-yl methyl 95.3-96.8 °C
64 5-chloropyrid-3-yl 2-fluoroethyl 125.9-126.9 °C
65 2,6-dichloropyrid-4-yl methyl 165-165.8 °C
66 2-chloro-6- hydrazinopyrid-4-yl methyl 72-73 °C
67 pyrid-4-yl methyl 74.5-76.1 °C
68 5-bromopyrid-3-yl methyl 144.1-145.2 °C
69 5-chloropyrid-3-yl vinyloxycarbonyl gum
70 5-chloropyrid-3-yl H 85-87 °C
71 6-chloropyrid-2-yl methyl 103.9-104.8 °C
72 5-chloropyrid-3-yl . 2,2,2-trifluoroethyl 109.5-111.5 °C
73 3,5-difluorophenyl pyrid-2-yl oil
74 5-chloropyrid-3-yl phenyl 122-123 °C
75 5-chloropyrid-3-yl propargyl 110-112 °C
76 5-chloropyrid-3-yl allyl 78-80 °C
AP/P/ 9 7/01 139 'Ί/A
Compound R1 R2 Melting Point
No 77 5-methoxypyrid-3-yl methyl 112.2-113.1 °C
78 5-chloropyrid-3-yl ethyl 116-118 °C
79 5-chloropyrid-3-yl butyl 48-50 °C
80 5-ethoxypyrid-3-yl methyl 567.2-57 °C
81 5-chloropyrid-3-yl hexyl resin
82 5-chloropyrid-3-yl phenoxycaibonyl 117-123 °C
83 5-chloropyrid-3-yl 2,2,2- oil
84 5-chloropyrid-3-yl trichloroethoxycarbonyl ethoxycarbonyl oil
85 5-chioropyrid-3-yl fluoren-9- 68-70 °C
86 5-chloropyrid-3-yl ylmethyloxycarbonyl ethoxycarbonylmethyl gum
87 5-chloropyrid-3-yl isopropyl oil
88 5-chloropyrid-3-yl 4,4,4-trifluorobut-3-on-l- 143.9-145.1 °C
89 5-chloropyrid-3-yl en-l-yl l-methyl-2,2,2- 152-155 °C
90 5-chloropyrid-3-yl trichloroethoxycarbonyl allyloxycarbonyl oil
91 5-chloropyrid-3-yl benzyloxycarbonyl oil
92 5-chloropyrid-3-yl 2-chloroethoxycarbonyl gum
93 5-chloropyrid-3-yl pentafluorobenzyl 143-144 °C
94 5-chloropyrid-3-yl 4-nitrophenyl 213-214.5 °C
95 5-chloropyiid-3-yl acetyl 162-165 °C
96 5-chloropyrid-3-yl trifluoroacetyl 121-124 °C
97 5-chloropyrid-3-yl 4-chlorobenzoyl 175-177 °C
98 5-chloropyrid-3-yl 4-fluorobenzoyl 200-204 °C
99 5-chloropyrid-3-yl 3-fluoropropyl oil
100 5-chloropyrid-3-yl 2,4-bis(trifluoro- 112-114 °C
101 5-chloropyrid-3-yl methyl)benzyl 4-carboxybenzyl gum
102 5-(prop- l-enyloxy)pyrid- methyl gum
103 3-yl 5-chloropyrid-3-yl 2,3-difluorobenzyl 102-103 °C
104 5-chloropyrid-3-yl 2-phenylethyl oil
105 5-chloropyrid-3-yl 4-cy anophenyl 201-204 °C
106 5-chloropyrid-3-yl 3,3-difluoroprop-2-en- 1-yl oil
107 5-chloropyrid-3-yl carboxymethyl 165-167 °C
108 5-chloropyrid-3-yl 3,5-dibromobenzy 1 194-196 °C
109 5-chloropyrid-3-yl 3-chloro-4-fluorobenzyl 95-97 °C
110 5-chloropyrid-3-yl formyl 141-142 °C
111 5-chloropyrid-3-yl isopropoxycarbonyl gum
112 5-chloropyrid-3-yl benzenesulfonyl 210-211 °C
113 5-chloropyrid-3-yl 2,4,6-trifluorobenzyl 106-107 °C
114 5-chloropyrid-3-yl 2,3,6-trifluorobenzyl 125-127 °C
115 5-chloropyrid-3-yl 1 -cyano-1 -phenylmethyl 141-142 °C
116 5-chloropyrid-3-yl methoxycarbonyl oil
AP.00803
Compound No R1 R2 Melting Point
117 5-chloropyrid-3-yl pyiid-2-yhnethyl 123-125 °C
118 5-chloropyrid-3-yl pyrid-3-ylmethyl 105-107 °C
119 5-chloropyrid-3-yl pyrid-4-ylmethyl 111-114 °C
120 pyrid-2-yl 2-fluoroethyl 82-84 °C
121 5-chloropyrid-3-yl (R)-1 -phenylethyl 115.6-116.7 °C
122 5-chloropyrid-3-yl (S)-l-phenylethyl 113.4-115 °C
123 5-chloropyrid-3-yl 2-methylthiazol-4-ylmethyl 81-83 °C
124 5-chloropyrid-3-yl 3,5-dimethylisoxazol-4ylmethyl 95-99 °C
125 5-chloropyrid-3-yl 5-chlorothien-2-ylmethyl 119-121 °C
126 5-chloropyrid-3-yl 5-trifluoromethylpyrid-2-yl 124.5-125.5 °C
127 pyrid-3-yl 2-methoxyethyl 251-253 °C
128 5-chloropyrid-3-yl 6-fluoropyrid-2-yl 131.5-132.5 °C
129 5-chloropyrid-3-yl 4-fluorophenyl solid
130 5-chloropyrid-3-yl 2,2,3,3,3-pentafluoropropy 1 oil
131 5-chloropyrid-3-yl 2,2,3,3-tetrafluoropropyl 110-113 °C
132 5-chloropyrid-3-yl 2,2,3,3,4,4,4- heptafluoropropyl oil
133 5-chloropyrid-3-yl 2,2,3,3,4,4,5,5- octafluoropropyl oil
134 5-aminopyrid-3-yl methyl 188-190 °C
135 5-chloropyrid-3-yl 1-phenyl-1carboxamidomethyl 193-195 °C
136 5-chloropyrid-3-yl 6-trifluoromethylpyrid-2-yl 117.5-118.5 °C
137 5-chloropyrid-3-yl 6-chloropyrid-2-yl 176-177 °C
138 5-chloropyrid-3-yl mercaptothiocarbonyl 224 °C
139 5-chloropyrid-3-yl t-butyl 127-129 °C
140 5-chloropyrid-3-yl 2-(ethoxycarbonyl)ethyl gum
141 5-chloropyrid-3-yl 2-caiboxyethyl 180-181 °C
142 5-chloropyrid-3-yl 2,2-difluoroethyl 101-104 °C
143 5-bromopyrid-3-yl 2,2,2-trifluoroethyl 105-110 °C
144 5-chloropyrid-3-yl fluorocarbonyl 165-167 °C
145 5-chloropyrid-3-yl N-methyl-N-phenyl carb amyl 108-110 °C
146 5-chloropyrid-3-yl N-t-butylcarbamyl 62-65 °C
147 5-iodopyrid-3-yl methyl 144-145 °C
148 5-hydroxypyrid-3-yl methyl 170.9-171.7 °C
149 5-chloropyrid-3-yl 4-morpholinocarbonyl 143-145 °C
150 5-chloropyrid-3-yl N,N-diisopropylcaibamyl 118-121 °C
151 5-chloropyrid-3-yl pentafluorophenyl gum
152 5-chloropyrid-3-yl 6-chloropyrimin-4-yl 174-176 °C
153 5-chloropyrid-3-yl 2-acetamidothiazol^l·- ylmethyl solid
154 5-chloropyrid-3-yl N-(3-chloro-4fluorophenyl) carbamyl 216-218 °C
155 5-chloropyrid-3-yl 5-chloropyrid-3-yl gum
£ I I 0 / L 6 /d/dV 1 ’ '1 Γ·
» jt5>[
Compound No R1 R2 Melting Point
156 5-chloropyrid-3-yl 4-trifluoromethylpyrid-3- carboxamidomethyl 149.3-1504 °C
157 5-chloropyrid-3-yl 4-trifluoromethylpyrid-3- ylcarbonyl 80.3-81.9 °C
158 5-chloropyrid-3-yl 5-chloro-1,2,3-tri adiazol-4ylmethyl oil
159 5-chloropyrid-3-yl 1 -formyl-1 -phenylethyl 124-126 °C
160 5-chloropyrid-3-yl 4,4,4-trifluorobutyl oil
161 5-methoxypyrid-3-yl 2,2,2-trifluoroethyl 88-90 °C
162 5-chloropyrid-3-yl 4-ethoxycarbonylphenyl 131.5-132.5 °C
163 5-chloro-6-fluoro pyrid3-yl 2,2,2-trifluoroethyl 121-122 °C
164 5-chloropyrid-3-yl vinyloxycarbonyl gum
165 5-acetamidopyrid-3-yl methyl 195-197 °C
166 5-methoxypyrid-3-yl cyanomethyl solid
167 5-chloropyrid-3-yl 3-chloromethyl-1,2,4thiadiazol-5-yl gum
168 5 -chloropyrid-3-yl 5-chlorothiazol-2-yl 111-112 °C
169 5 -chloropyrid-3-y 1 cyano 168-170 °C
170 5 -chloropyrid-3-y 1 4-carboxyphenyl solid
171 5-methoxypyrid-3-y 1 vinyloxycarbonyl gum
172 5-methoxypyrid-3-yI H 112-114 °C
173 5-chloropyrid-3-yl 4-chlorophenyl 137.5-138 °C
174 5-trifluoromethylpyrid-3- yi 5-chloropyrid-3-yl methyl 118.2-118.5 °C
175 2-phenylbut-3-en-2-yl gum
176 5-chloropyrid-3-yl 3-hydroxy-2-phenylprop-2- yi formyl 124-126 °C
177 5-trifluoromethylpyrid-3- yi 5-chloropyrid-3-yl 117-121 °C
178 3-acetoxy-2-phenylprop-2- yi 2-fluoro-2-phenylprop-1 -y 1 130-131 °C
179 5-chloropyrid-3-yl gum
180 5-chloropyrid-3-yl 3,3,5-trimethylhexy 1
181 5-bromopyrid-3-yl vinyloxycarbonyl 63-66 °C
182 5-chloropyrid-3-yl pyrimid-2-yl; 148.5-149.5 °C
183 5-trifluoromethylpyrid-3- yi 5-trifluoromethylpyrid-3 yi pyrid-3-yd vinyloxycarbonyl resin
184 H resin
185 vinyloxycarbonyl gum
186 5-trifluoromethy lpyrid-3 yi 5-chloropyrid-3-yl 3-chlorobenzyl oil
187 2-chloropyrimid-4-yl 210-212 °C
188 5-chloropyrid-3-yl 4-trifluoromethylphenyl 131-132 °C
189 5-(pyrrol-1 -yl)pyrid-3-yl methyl gum
AP. ο 08 Ο 3
Compound No R1 R2 Melting Point
190 N-oxidopyrid-3-yl t-butoxycarbonyl 55-57 °C
191 5-chloropyrid-3-yl 2-phenyl-2- isopropylaminoprop-1 -yl gum
192 5-chloropyrid-3-yl 2-phenyl-3-hydroxy-3- cyanoprop-2-yl 172-175 °C
193 5-ethynylpyrid-3-yl methyl solid
194 pyrimid-4-yl methyl solid
195 5-( l-ethoxyvinyl)pyrid-3- yi pyrid-3-yl methyl - gum
196 1,1 -dimethylpropy 1 gum
197 5-chloropyrid-3-yl 1 -ethoxycarbonylethy 1 gum
198 5-bromopyrimid-4-yl methyl 141-145 °C
199 5- trifluoromethylpyrid-3yi 6- pyrimid-4-ylpyrimid-4yi 5-acetylpyrid-3-yl 2,2,2-trifluoroethyl gum
200 methyl 136-154 °C
201 methyl gum
202 5-fluoropyrid-3-yl methyl 135-137 °C
203 5-bromopyrid-3-yl H 128-130 °C
204 5-bromopyrid-3-yl 2-chlorobenzyl 109-111 °C
205 5-chloropyrid-3-yl 2-(3-chlorophenyl)prop-2- yi methyl gum
206 5-(2-hydroxyprop-2- yl)pyrid-3-yl gum
207 5-chloropyrid-3-yl 2-methylbut-3-yn-2-yl 107-110 °C
208 5-bromopyrid-3-yl ethoxycarbonyl 92-94 °C
209 5-chloropyrid-3-yl 2-methy 1-1,1,1 trifluoroprop-2-yl 97-99 °C
210 5-bromopyrid-3-yl 2-methylpropyl oil
211 5-chloropyrid-3-yl 1 -methoxycarbony lethyl (Isomer A) gum
212 5-chloropyrid-3-yl 1-methoxycarbony lethyl (racemate) 105-106 °C
213 5-chloropyrid-3-yl 1 -methoxycarbony lethyl (Isomer B) gum
214 6-methoxypyrazin-2-yl methyl gum
215 5-chloropyrid-3-yl 1-cyano-1-(3chlorophenyl)methyl foam
216 5-chloropyrid-3-yl 1-cyanoethyl gum
217 5-phenylpyrid-3-yl vinyloxycarbonyl gum
218 5-chloropyrid-3-yl 4,4-difluorobut-3-en-1 -yl oil
219 5-chloropyrid-3-yl 1 -cy ano-2-methylprop-1 -yl gum
220 5-phenylpyrid-3-yl H gum
221 5-methylpyrid-3-yl vinyloxycarbonyl gum
222 5-ethoxycarbonylpyrid-3- yi 5-chloropyrid-3-yl vinyloxycarbonyl solid
223 2-cyanoprop-2-yl solid
AP/P/ 97 / 0 1139
Compound No 224 R1 R2 Melting Point
6-ethynylpyrazin-2-yl methyl solid
225 5-ethoxycarbonylpyrid-3- yi 5-(2,2,2- - trifluoroethoxy)pyrid-3-yl H gum
226 trifluoroethyl oil
227 5-chloropyrid-3-yl 3,5- bis(trifluoromethyl)benzyl
228 5-chloropyrid-3-yl 2,6-difluorobenzyl
229 5-chloropyrid-3-yl 3-phenoxybenzyl
230 5-chloropyrid-3-yl 3-bromo-4-fluorobenzyl
231 5-chloropyrid-3-yl 3-benzoylbenzvl
232 5-chloropyrid-3-yl 3-(2,6- dichlorobenzoy 1 )benzy 1
233 5-chloropyrid-3-yl 3-(2,6- difluorobenzoyl)benzyl
234 5-chloropyrid-3-yl 4-allyl-2,3,5,6- tetrafluorobenzyl
235 5-chloropyrid-3-yl 3-trifluoromethoxybenzyl
236 5-chloropyrid-3-yl naphth-1 -ylmethyl
237 5-chloropyrid-3-yl benzyl
238 5-chloropyrid-3 -yl 2-bromobenzyl
239 5-chloropyrid-3-yl 2-methylbenzyl
240 5-chloropyrid-3-yl 3-bromobenzyl
241 5-chloropyrid-3-yl 3-methoxycarbonylbenzyl
242 5-chloropyrid-3-yl 3-methylbenzyl
243 5-chloropyrid-3-yl 4-bromobenzyl
244 5-chloropyrid-3-yl 4-methoxycarbonylbenzyl
245 5-chloropyrid-3-yl 4-t-butylcarbonylbenzyl
246 5-chloropyrid-3-yl 4-t-butylbenzyl
247 5-chloropyrid-3-yl 4-isopropylbenzyl
248 5-chloropyrid-3-yl 4-methylbenzyl
249 5-chloropyrid-3-yl 3,4-difluorobenzy 1
250 5-chloropyrid-3-yl 2-fluorobenzyl
251 5-chloropyrid-3-yl 3-bromo-5-fluorobenzyl
252 5-chloropyrid-3-yl 2,4-difluorobenzyl
253 5 -chloropyrid-3-yl 3-fluorobenzyl
254 5-chloropyrid-3-yl 4-fluorobenzyl
255 5-chloropyrid-3-yl 3-trifluoromethylbenzyl
256 5-chloropyrid-3-yl 4-trifluoromethylbenzyl
257 5-chloropyrid-3-yl 2-fl uoro-3-chlorobenzy 1
258 5-chloropyrid-3-yl 2-chloro-3,6-difluorobenzyl
259 5-chloropyrid-3-yl 2-chlorobenzyl
260 5-chloropyrid-3-yl 2,6-dichlorobenzyl
261 5-chloropyrid-3-yl 3-chlorobenzyl
262 5-chloropyrid-3-yl 2-iodo-4-fluorobenzyl 108-109 °C
263 5-chloropyrid-3-yl 2-fluoro-3-methylbenzyl
264 5-chloropyrid-3-yl 2-(N-succinimido)benzyl
AP. Ο ο 8 ο 3
Compound R* R2 Melting Point
No
265 5-chloropyrid-3-yl 2-fluoro-5- trifluoromethylbenzyl
266 5-chloropyrid-3-yl biphenyl-2-ylmethyl
267 5-chloropyrid-3-yl 2-cyanobenzyl
268 5-chloropyrid-3-yl 4-( 1,2,3-thiadiazol-4yl)benzyl
269 5-chloropyrid-3-yl 3-(4-fluorophenoxy)benzyl
270 5-chJoropyrid-3-yl 4-cyanobenzyl
271 5-chloropyrid-3-yl 2,3,4-trifluorobenzyl
272 5-chloropyrid-3-yl 2-nitrobenzyl
273 5-chloropyrid-3-yl 2-nitro-6-fluorobenzyl
274 5-chloropyrid-3-yl 3-nitrobenzyl
275 5-chloropyrid-3-yl 4-nitrobenzyl
276 5-chloropyrid-3-yl 2-methylprop-1 -yl
277 5-chloropyrid-3-yl decyl
278 5-chloropyrid-3-yl 2-phenoxyethyl
279 5-chloropyrid-3-yl 2-ethoxyethyl
280 5-chloropyrid-3-yl 3-methylbut-l-yl
281 5-chloropyrid-3-yl 3-methoxycarbonylprop-1 yi 3-phenylprop-1 -yl
282 5-chloropyrid-3-yl
283 5-chloropyrid-3-yl cyclohexylmethyl
284 5-chloropyrid-3-yl 2-cy anoethyl
285 5-chloropyrid-3-yl 3-cyanoprop-l-yl
286 5-chloropyrid-3-yl 2-hydroxyprop-1 -y 1
287 5-chloropyrid-3-yl 2-propenoyloxyethyl
288 5-chloropyrid-3-yl 2-methoxyethyl
289 5-chloropyrid-3-yl tetrahydropyran-2-ylmethyl
290 5-chloropyrid-3-yl 2-hy droxymethylprop-1 -yl
291 5-chloropyrid-3-yl diethylphosphonomethyl 69-70 °C
292 5-chloropyrid-3-yl phosphonomethyl 242-245 °C
293 5-chloropyrid-3-yl methyl (N-oxide) 153-155 °C
294 pyrid-3-yl t-butoxycarbaryl
295 6-choloropyrid-3-yl H
296 5-chloropyrid-3-yl methoxy
297 2-chloropyrimid-4-yl 2,2,2-trifluoroethyl
'298 6-chloropyrazin-2-yl vinyloxycarbonyl
299 6-chloropyrazin-2-yl H
300 6-chloropyrazin-2-yl 3-chlorobenzyl
301 6-chloropyrazin-2-yl cy anomethyl
302 5-chloropyrid-3-yl 1 -(3-chlorophenyl)ethyl
303 5-chloropyrid-3-yl 4-methoxyphenyl
304 5-cyanopyrid-3-yl methyl
305 2-chloropyrid-4-yl methyl
306 5-chloropyrid-3-yl 2-phenylprop-1-en-1-yl
307 5-chloropyrid-3-yl methylmercaptothio- carbonyl
ΑΡ/Ρ/9 7/0 1 1 39 η
Compound No R1 R2 Melting Point
308 5-(2,2,2-trifluoro- ethoxy)pyrid-3-yl methyl
309 5-iodopyrid-3-yl vinyloxycarbonyl
It will be appreciated that the bicyclic amine compounds of formula I arc capable of existing in more than one isomeric form since the groups R1 and R2 may be positioned in either an exo or endo relationship, and the present invention embraces within its scope both exo and endo forms and mixtures thereof and also any further isomeric variants arising from cis and trans substitution patterns or chiral centres present in either of R1 or R*.
Suitable acid addition salts include those with an inorganic acid such as hydrochloric, hydrobromic, sulfuric, nitric and phosphoric acids, or an organic carboxylic acid such as oxalic, tartaric, lactic, butyric, toluic, hexanoic and phthalic acids, or sulphonic acids such as methane, benzene and toluene sulphonic acids. Examples of salts of compound 72 (Table I) with some less common acids are given in Table IA.
TABLE IA
Compound No
310
311
312
313
314
315
316
317
318
319
320
321
Acid Component
2- chlorobenzoic acid
4-chloropnenoxyacetic acid
2,4,6-trimethylbenzoic acid
3- benzylbenzoic
4- hydroxybenzoic acid
1- phenylpropionic acid
3- (4-hydroxyphenyl)propenoic acid undecanoic acid
4- (4-hydroxyphenyl)butyric acid
2- hvdroxv-5-nitrobenzoic acid * X
-ni tro-5-N-me thy iformami dobe nzoic acid
2,2,3,3-tetramethylcyclopropanoic acid
The preparation of the compounds of formula (I) may be accomplished by use of one or more of the following synthetic techniques described below and further illustrated in the Examples.
The compounds of general formula (I) can be prepared from compounds of general formula (Π) by treating them with a suitable base, such as potassium carbonate, in the presence of compound ot formula R*L where L is a suitable leaving group such as a halide or tri flate.
AP. ο ο 8 Ο 3
- 11 Alternatively, compounds of general formula (I) can be prepared from compounds of general formula (Π) by reductive amination with an aldehyde (R3CHO; where R3CH2=R2) in the presence of a suitable reducing agent such as formic acid.
Compounds of general formula (Π) can be prepared by demethylating compound of 5 general formula (HI) by, for instance, treating them first with a chloroformate ester (such as vinyl chloroformate) to produce a carbamate, followed by acid hydrolysis.
Compounds of general formula (IH) can be prepared by treating 3-cyano-8-methyl-8azabicyclo[3.2. ljoctane (TV) first with a suitable base, such as lithium diisopropylamide (LDA), followed by reaction with an aryl or heteroaryl halide (R’Hal).
3-Cyano-8-methyl-8-azabicyclo[3.2.1]octane (IV) can be prepared by treating tropinone (V) with tosylmethyl isocyanide in the presence of a suitable base, such as potassium ethoxide. As an alternative 3-cyano-8-methyl-8-azabicyclo[3.2. ljoctane (IV) can be prepared from tropine (XIII) by treatment with thionyl chloride to give alternative 3-chloro8-methyl-8-azabicyclo[3.2. ljoctane (XII) followed by treatment with cyanide as described in
J. Am. Chem. Soc., 1958 80,4677.
As an alternative, compounds of general formula (I) can be prepared from compounds t
of general formula (VI) by treatment with a suitable base, such as lithium diisopropylamide (LDA), followed by reaction with an aryl or heteroaryl halide (R’Hal).
Compounds of general formula (VI) can be prepared from 3-cyano-820 azabicyclo[3.2.1joctane (VH) by treatment with a suitable base, such as potassium carbonate, in the presence of an alkyl halide (RxHal).
3-Cyano-8-azabicvclo[3.2. ljoctane (VH) can be prepared by demethylating 3-cyano-8methyl-8-azabicyclo[3.2. ljoctane (IV) by, for instance, treatment first with a chloroformate ester (such as vinyl chloroformate) to produce a carbamate, followed by acid hydrolysis.
Asa further alternative, compounds of general formula (VI) can be prepared by treating compounds of general formula (VHI) with tosylmethyl isocyanide in the presence of a suitable base, such as potassium ethoxide.
Compounds of general formula (VHI) can be prepared by the Robinson tropinone synthesis, see, for instance, J. Chem. Soc., 1917, 111, 762. As an alternative compounds of general formula (VHI) can be prepared from cyclohepta-2,6-dienone (XT) by reaction with an amine ,(R:NH2) as described in, for instance. Tetrahedron, 1973,155, Bull, Chem, Chem, Soc,
Jpn., 1971,44, 1708 and J. Org. Chem., 1971,36, 1718.
AP/P/ 9 7/01 139
- 12 As yet a further alternative, compounds of general formula (I) can be prepared by treatment of a compound of general formula (IX) with an aryl- or heteroaryl-ticetonitrile of general formula (X) in the presence of a suitable base, such as sodium hydride, as described in J. Med. Chem., 1975, 18,496.
The compound of general formula ( VI) (except those Wherein R represents methyl, benzyl or trichloroethyl) are believed not to have been previously described. Accordingly in a further aspect the invention provides compounds of formula (VI) wherein R2 represents hydrogen or cyano or a group selected from alkyl, aryl, hetroaryl, aralkyl, hetroarylalkyl, alkenyl, aralkenyl, alkynyl, alkoxycarbonyl, alkanesulfonyl, arenesulfonyl, alkanyloxycarbonyl,
IO. aralkyloxycarbonyl, aryloxycarbonyi, hertocyclylalkyl, carbamyl or dithiocarboxyl groups, said groups comprising from 1 to 15 carbon atoms, said groups being optionally substituted with one or more substituents selected from, halogen, cyano, carboxyl, carboxylic acyl, arbamyl, alkoxycarbonyl, alkoxy, alkylenedioxy, hydroxy, nitro, haloalkyi, alkyl, amino, acyclamino, imidate and phosphonato groups; and acid addition salts, quaternary ammonium salts and N1 S'. oxides derived therefrom; with the proviso that R2 is not methyl, 3-methylbutyl, n-hexyl, cyclohexylmethyl, benzyl, 4-chlorobenzvl, 4-methylbenzyl, 4-methoxybenzvl, 3,4dichlorobenzyl, 3-trifluromethylbenzyl, 2-phenethyl, 2-thienyl or trichloroethyl.
In a further aspect the invention provides a method of combating insect and like pests at a locus by applying to the locus or the pests an insecticidaliy-effective
20. amount of an insecticidal composition comprising the compounds of Formula I or an acid addition salt thereof.
The compounds of Formula I and acid addition salts thereof may be used to combat and control infestations of insect pests such as Lepidoptera, Diptera, Homoptera and Coleoptera (including Diabrotica i.e. com rootworms) and also other invertebrate pests, for example,
2.S. acarine pests. The insect and acarine pests which may be combated and controlled by the use of the invention compounds include those pests associated with agriculture (which term includes the growing of crops for food and fibre products), horticulture and animal husbandry, forestry, the storage of products of vegetable origin, such as fruit, grain and timber, and also those pests associated with the transmission of diseases of man and animals. Examples of
3o . insect and acarine pest species which may be controlled by the compounds of Formula I include:'
AP. ο Ο 8 ο 3
- 12a Mvzus persicae (aphid), Aphis gossypii (aphid), Aphis fabae (aphid), Aedes aegypti (mosquito), Anopheles spp. (mosquitos), Culex spp. (mosquitos), Dvsdercus fasciatus (capsid), Musca domestica (housefly), Pieris brassicae (white butterfly), Plutella xvlostella (diamond back moth), Phaedon cochleariae (mustard beetle), Aonidiella spp. (scale insects), Trialeurodes spp. (white flies), Bemisia tabaci (white fly), Blattella germanica (cockroach), Periplaneta americana (cockroach), Blatta orientalis (cockroach) Spodoptera littoralis (cotton leafworm), Heliothis virescens (tobacco budworm) Chortiocetes terminifera (locust),
Diabrotica spp. (rootworms), Agrotis spp. (cutworms), Chilo partellus (maize stem borer), Nilaparvata lugens (planthopper), Nephotettix cincuceps (leafhopper), Panonvchus ulmi (European red mite), Panonvchus citri (citrus red mite), Tetranychus urticae (two-spotted
AP/P/ 9 7/01 139
AP. Ο Οθο 3
- 13 spider mite), Tetranychus cinnabarinus (carmine spider mite), Phvllcoptruta oleivora (citrus rust mite), Polyphagotarsonemus latus (broad mite) and Brevipaipus spp. (mites).
In order to apply the compounds of Formula I to the locus of the nematode, insect or acarid pest, or to a plant susceptible to attack by the nematode, insect or acarid pest, the compound is usually formulated into a composition which includes in addition to the the compounds of Formula I suitable inert diluent or carrier materials, and/or surface active agents. The amount of composition generally applied for the control of nematode pests gives a rate of active ingredient from 0.01 to 10 kg per hectare, preferably from 0.1 to 6 kg per hectare.
The compositions can be applied to the soil, plant or seed, to the locus of the pests, or to the habitat of the pests, in the form of dusting powders, wettable powders, granules (slow or fast release), emulsion or suspension concentrates, liquid solutions, emulsions, seed dressings, fogging/smoke formulations or controlled release compositions, such as microencapsulated granules or suspensions.
Dusting powders are formulated by mixing the active ingredient with one or more Finely divided solid carriers and/or diluents, for example natural clays, kaolin, pyrophyllite, bentonite, alumina, montmorillonite, kieselguhr, chalk, diatomaceous earths, calcium phosphates, calcium and magnesium carbonates, sulphur, lime,' flours, talc and other organic and inorganic solid carriers.
Granules are formed either by absorbing the active ingredient in a porous granular ’ material for example pumice, attapulgite clays, fuller's earth, kieselguhr, diatomaceous earths, ground com cobs, and the like, or on to hard core materials such as sands, silicates, mineral carbonates, sulphates, phosphates, or the like. Agents which are commonly used to aid in impregnation, binding or coating the solid carriers include aliphatic and aromatic petroleum solvents, alcohols, polyvinyl acetates, polyvinyl alcohols, ethers, ketones, esters, dextrins, sugars and vegetable oils, with the active ingredient. Other additives may also be included, such as emulsifying agents, wetting agents or dispersing agents.
Microencapsulated formulations (microcapsule suspensions CS) or other conmolled release formulations may also be used, particularly for slow release over a period of time, and for seed treatment.
Alternatively the compositions may be in the form of liquid preparations to be used as dips, irrigation additives or sprays, which are generally aqueous dispersions or emulsions of
AP/P/ 9 7/01 139
- 14 the active ingredient in the presence of one or more known wetting agents, dispersing agents or emulsifying agents (surface active agents). The compositions which are to be: used in the form of aqueous dispersions or emulsions are generally supplied in the form of an emulsifiable concentrate (EC) or a suspension concentrate (SC) containing a high proportion of the active ingredient or ingredients. An EC is a homogeneous liquid composition, usually containing the active ingredient dissolved in a substantially non-volatile organic solvent. An SC is a fine particle size dispersion of solid active ingredient in water. To apply the concentrates they are diluted in water and are usually applied by means of a spray to the area to be treated.
Suitable liquid solvents for ECs include methyl ketone, methyl isobutyl ketone, cyclohexanone, xylenes, toluene, chlorobenzene, paraffins, kerosene, white oil, alcohols, (for example, butanol), methylnaphthalene, trimethylbenzene, trichloroethylene, N-methyl-2-pyrrolidone and tetrahydrofurfuryl alcohol (THFA).
Wetting agents, dispersing agents and emulsifying agents may be of the cationic, anionic or non-ionic type. Suitable agents of the cationic type include, for example, quaternary ammonium compounds, for example cetyltrimethyl ammonium bromide. Suitable agents of the anionic type include, for example, soaps, salts of aliphatic monoesters of sulphuric acid, for example sodium lauryl sulphate, salts of sulphonated aromatic compounds, for example sodium dodecylbenzenesulphonate, sodium, calcium or ammonium lignosulphonate, or butylnaphthalene sulphonate, and a mixture of the sodium salts of diisopropyl- and triisopropylnaphthalene sulphonates. Suitable agents of the non-ionic type include, for example, the condensation products of ethylene oxide with fatty alcohols such as oleyl alcohol or cetyl alcohol, or with alkyl phenols such as octyl phenol, nonyl phenol and octyl cresol. Other non-ionic agents are the partial esters derived from long chain fatty acids and hexitol anhydrides, the condensation products of the said partial esters with ethylene oxide, and the lecithins.
These concentrates are often required to withstand storage for prolonged periods and after such storage, to be capable of dilution with water to form aqueous preparations which remain homogeneous for a sufficient time to enable them to be applied by conventional spray equipment. The concentrates may contain 10-85% by weight of the active ingredient or ingredients. When diluted to form aqueous preparations such preparations may contain varying amounts of the active ingredient depending upon the purpose for which they are to be used.
AP.00803
- 15 The compounds of Formula I may also be formulated as powders (dry seed treatment DS or water dispersible powder WS) or liquids (flowable concentrate FS, liquid seed treatment LS, or microcapsule suspension CS) for use in seed treatments.
In use the compositions are applied to the insect pests, to the locus of the pests, to the 5 habitat of the pests, or to growing plants liable to infestation by the pests, by any of the known means of applying pesticidal compositions, for example, by dusting, spraying, or incorporation of granules.
The compound of Formula I may be the sole active ingredient of the composition or they may be admixed with one or more additional active ingredients such as insecticides, synergists, herbicides, fungicides or plant growth regulators where appropriate.
Suitable additional active ingredients for inclusion in admixture with a compound of Formula I may be compounds which will broaden the spectrum of activity of the compositions of the invention or increase their persistence in the location of the pest. They may synergise the activity of the compound of Formula I or complement the activity for example by increasing the speed of effect or overcoming repellency. Additionally multi-component mixtures of this type may help to overcome or prevent the development of resistance to individual components. The particular additional active ingredient included will depend upon the intended utility of the mixture and the type of complementary action required. Examples of suitable insecticides include the following:
a) Pyrethroids such as permethrin, esfenvalerate, deltamethrin, cyhalothrin in particular lambda-cyhalothrin, biphenthrin, fenpropathrin, cyfluthrin, tefluthrin, fish safe pyrethroids for example ethofenprox, natural pyrethrin, tetramethrin, s-bioallethrin, fenfluthrin, prallethrin and 5-benzyl-3-furyimethyl-(E)-(lR,3S)-2,2-dimethyl- 3-(2-oxothiolan-3-ylidenemethyl) cyclopropane carboxylate;
b) Organophosphates such as profenofos, sulprofos, methyl parathion, azinphos-methyl, ν demeton-s-methyl, heptenophos, thiometon, fenamiphos, monocrotophos, profenophos, triazophos, methamidophos, dimethoate, phosphamidon, malathion, chloropyrifos, phosalone, terbufos, fensulfothion, fonofos, phorate, phoxim, pyrimiphos-methyl, pyrimiphos-ethyl, fenitrothion or diazinon;
c) Carbamates (including aryl carbamates) such as pirimicarb, cloethocarb, carbofuran, furathiocarb, ethiofencarb, aldicarb, thiofurox, carbosulfan, bendiocarb, fenobucarb, propoxur or oxamyl;
AP/P/ 9 7/01139
- 16 d) Benzoyl ureas such as triflumuron, or chlorfluazuron;
e) Organic tin compounds such as cyhexatin, fenbutatin oxide, azocyclotin;
f) Macrolides such as avermectins or milbemycins, for example such as abamectin, ivermectin, and milbemycin;
g) Hormones and pheromones;
h) Organochlorine compounds such as benzene hexachloride, DDT, chlordane or dieldrin;
i) Amidines, such as chlordimeform or amitraz;
j) Fumigant agents;
k) Lmidacloprid.
In addition to the major chemical classes of insecticide listed above, other insecticides having particular targets may be employed in the mixture if.appropriate for the intended utility of the mixture. For instance selective insecticides for particular crops, for example stemborer specific insecticides for use in rice such as cartap of buprofezin can be employed.
Alternatively insecticides specific for particular insect species/stages for example ovo-larvicides such as chlofentezine, flubenzimine, hexythiazox and tetradifon, motilicides such as dicofol or propargite, acaricides such as bromopropylate, chlorobenzilate, or growthregulators such as hydramethyiron, cyromazine, methoprene, chlorofluazuron and diflubenzuron may also be included in the compositions.
Examples of suitable synergists for use in the compositions include piperonyl butoxide, sesamax, saffoxan and dodecyl imidazole.
Suitable herbicides, fungicides and plant-growth regulators for inclusion in the compositions will depend upon the intended target and the effect required.
An example of a rice selective herbicide which can be included is propanil, an example of a plant growth regulator for use in cotton is Pix”, and examples of fungicides for use in rice include blasticides such as blasticidin-S. The ratio of the compounds of Formula I to the other active ingredient in the composition will depend upon a number of factors including type of target, effect required from the mixture etc. However in general, the additional active ingredient of the composition will be applied at about the rate as it is usually employed, or at a slightly lower rate if synergism occurs.
The invention is illustrated by the following examples. Examples (except example 5) to 86 illustrate the preparation of a range of compounds of formula (I).
AP. Ο Ο 8 ο 3
- 17 Examples 87 - 104 (except example 101) illustrate formulations suitable for the application of the compounds of Formula I according to the invention. The following ingredients are referred to by their Registered Trade Marks and have the composition as shown below.
Registered Trade Mark Composition Synperonic NP8 } Nonylphenol-ethylene oxide condensate
Synperonic NP13 Synperonic ΟΡΙΟ Aromasol H Solvesso 200 Keltrol
Alkylbenzene solvent 10 Solvesso 200 Inert organic diluent
Polysaccharide
EXAMPLE 1
This example illustrates the preparation of' exo-3-(pyrid-3-yD-endo-3-cyano-8-rrethy1-Sazabicyclo[3.2.1]octane.
Potassium t-butoxide (22.4g) was added portionwise to a stirred mixture of tropinone (11.58g) and tosylmethyl isocyanide (21.2g) in dimethoxyethane (240ml) and ethanol (8ml) al 0°C under nitrogen at such a rate to maintain the temperature between 0°C and 10°C. The mixture was then allowed to warm to room temperature and stirred for a further 4 hours. After standing at room temperature for 3 days the mixture was filtered and the solid residue washed with dimethoxyethane. The filtrate was evaporated under reduced pressure and chromatographed [SiQ,; dichloromethanermethanol (90:10)] to give exo-3-cyano-8-roethyI-8-azabicyclo[3.2.1]octane (9.1g).
exo-3-Cyano-8-methyl-8-azabicyclo[3.2.1 joctane (lO.Og) in tetrahydrofuran (60ml) was added dropwise to a stirred solution of lithium diisopropylamide [made by adding n-BuLi (29ml of a k2.5M solution in hexane) to diisopropylamine (10ml) in tetrahydrofuran (60ml)] at -25°C under nitrogen. The mixture was stirred at -25°C for 20 minutes and then cooled to -78°C. 3Fluoropyridine (lO.Og) in tetrahydrofuran (60ml) was then added dropwise. The mixture was then allowed to warm to room temperature over 6 hours. The mixture was then poured into water and extracted with dichloromethane. The combined extracts were washed with brine, dried (MgSCL), evaporated under reduced pressure and chromatographed [SiOy, dichloromethane-.methanol (80:20)] to give a yellow oil which crystallised on standing. The solid was washed with hexane
AP/P/ 9 7/01 139 and ether, filtered and air-dried to give exo-3-(pyrid-3-yI)-endo-3-cyano-8-methyi-8azabicyclo[3.2.1]octane (8.2g).
EXAMPLE 2
This example illustrates the preparation of exo-3-(pyrid-3-yl)-endo-3-cyano-8-(2-fluoroethyl)-8azabicyclo[3.2.1 Joctane.
Vinyl chloroformate (6.0mi) in tetrahydrofuran (10ml) was added dropwise to exo-3-(pyrid-3-vl)endo-3-cyano-8-methyl-8-azabicyclo[3.2.1 Joctane (4.0g) in tetrahydrofuran (40rnl) at 0°C under nitrogen. The mixture was then healed at 70°C for 4.5 hours. After cooling to room temperature the mixture was filtered and the solid residue washed with ethyl acetate. The combined filtrates were evaporated under reduced pressure and crystallised on standing to give exo-3-(pyrid-3-yl)endo-3-cyano-8-(vinyloxycarbonyl)-8-azabicyclo[3.2.1 Joctane (4.1 g).
exo-3-(Pyrid-3-yl)-endo-3-cyano-8-(vinyloxycarfaonyl)-8-azabicycloi3.2.1 ]octane (3.5g) and concentrated hydrochloric acid (3ml) in methanol (25 ml) were refluxed for 6 hours and then allowed to stand at room temperature overnight. After the mixture had been refluxed for a further 4 hours it was allowed to cool to room temperature and then evaporated under reduced pressure. The mixture was then partitioned between 2M sodium hydroxide and ethyl acetate and the aqueous layer was separated and extracted with ethyl acetate. The combined organic fractions were washed with brine, dried (MgSO4)' and evaporated under reduced pressure to give exo-3(pvrid-3-vD-endo-3-cyano-8-azabicyclo[3.2.1 joctane (1.7g), which crystallised on standing.
exo-3-(Pyrid-3-yl)-endo-3-cyano-8-azabicycio[3.2.1 Joctane (0.2g), 1 -bromo-2-fiuoroethane (0.21ml), potassium carbonate (0.14g) and tetrahydrofuran (6ml) were heated at 60°C for 6.5 hours and then allowed to stand at room temperature overnight. l-Bromo-2-fiuoroethane (0.2ml) was then added and the mixture heated at 60°C for 6 hours, cooled to room temperature, filtered and evaporated under reduced pressure. Chromatography [SiO2; dichloromethane:methanol (90:10)] gave exo-3-(pyrid-3-yl)-endo-3-cyano-8-(2-f3uoroethyl)-8-azabicyclo[3.2.1]octane (0.123g) m.p. 84.4°C.
EXAMPLE 3
This example illustrates the preparation of exo-3-(3.5-difluorophenyl)-endo-3-cyano-8-methyl8-azabicyclo[3.2.1 Joctane.
exo-3-Cyano-8-methyl-8-azabicyclo[3.2.1 Joctane (13.6 g in tetrahydrofuran (80 ml) was added dropwise to a stirred solution of lithium diisopropylamide [made by adding n-BuLi (40ml of a
AP.00803
- 19 2.5M solution in hexane) to diisopropvlamine (14.0ml) in tetrahydrofuran (80ml)] at -25°C under nitrogen. Tbs mixture was stirred at -25°C for 0.5 hours and then cooled to -78°C. 1,3,5Trifluorobenzene (12.0g) in tetrahydrofuran (80ml) was added dropwise at such a rate to maintain the temperature below -65 °C. The mixture was allowed to warm to room temperature overnight and then poured into water and extracted with dichloromethane. The combined extracts were washed with brine, dried (MgSO4) and evaporated under reduced pressure to give a yellow solid. This was recrystallised from diethyl ether to give exo-3-(3.5-difluorophenyl)-endo-3-cyano-8methyl-8-azabicyclo[3.2.1]octane. The mother liquor from the recrystallisation was chromatographed [S1O2; dichloromethanermethanol (90:10)] to give further exo-3-(3.5-; .40 difiuorophenyl)-endo-3-cyano-8-methyl-8-azabicyclo[3.2.1 ]octane (11.2g in total).
EXAMPLE 4
This example illustrates the preparation of exo-3-(pyrid-3-yl)-endo-3-cyano-8-(prop-1 -vD-8azabicyclo[3.2. l]octane.
Vinyl chloroformate (2.5ml) in diethyl ether (15ml) was added dropwise to a stirred mixture of exo-3-cyano-8-methvl-8-azabicycloi3.2.11octane (3.0g) in diethyl ether (15ml) at -5°C under nitrogen. The mixture was then stirred at 0°C for 0.5 hours and at reflux for 5 hours. After cooling to room temperature the mixture was filtered and the solid residue washed with diethyl ether. The combined filtrates were evaporated under reduced pressure to give exo-3-cyano-820 (vinyloxycarbonyl)-8-azabicyclo[3.2.1]octane (2.93g).
exo-3-Cyano-8-(vinyloxycarbonyl)-8-azabicyclo[3.2.1]octane (2.9g), concentrated hydrochloric acid (1ml) and methanol (30ml) were refluxed for 4 hours and then allowed to stand at room temperature overnight. Concentrated hydrochloric acid (1ml) was added and the mixture refluxed for 4 hours. After cooling to room temperature the mixture was evaporated under reduced pressure, dissolved in ethyl acetate and washed with 2M sodium hydroxide and brine, dried (MgSO4) and evaporated under reduced pressure to give exo-3-cyano-8-azabicyclo[3.2.l]octane (1.09g) as a dark yellow solid.
exo-3-Cyano-8-azabicyclo[3.2.1]octane (0.5g), 1-bromopropane (0.34ml) and potassium carbonate (1.27g) were stirred in ethanol (5ml) at room temperature for 5 hours. 130 Bromopropane (0.17ml) was then added and the mixture stirred overnight. 1-Bromopropane (0.17ml) was added and the mixture stirred at room temperature for 6 hours, a further portion of
1-bromopropane (0.17ml) was added and the mixture allowed to stand at room temperature for 3
AP/P/ 9 7/01139 days and then refluxed for 0..5 hours. The mixture was then cooled to room temperature, filtered and the filtrate evaporated under reduced pressure. Chromatography [SiO^; dichloromethane:methanol (90:10)] gave exo-3-cyano-8-propyl-8-azabicvcloi3.2.1 loctane (0.39g). exo-3-Cvano-8-propvl-8-azabicvclo[3.2.11octane (0.32g) in tetrahydrofuran 92,ml) was added dropwise to a stirred solution of lithium diisopropylamide [made by adding n-BuLi (0.8ml of a 2.5M solution in hexane to diisopropylamine (0.2ml) in tetrahydrofuran (2ml)] at -25°C under nitrogen. The mixture was stirred at -25°C for 0.5 hours, cooled to -76°C and 3-fluoropyridine (0.175g) in tetrahydrofuran (2ml) was added dropwise. The mixture was stirred at -76°C for 1 hour and then allowed to warm slowly to room temperature and allowed to stand overnight. The mixture was poured into water, extracted with ethyl acetate (x3) and the combined extracts washed with brine and water, dried (MgSCL) and evaporated under reduced pressure. Chromatography [SiO2; dichloromethanetmethanol (95:5)] gave exo-3-(pvrid-3-yl)-endo-3-cvano8-(prop- l-yl)-8-azabicyclo[3.2. l]octane (0.35g).
EXAMPLE 5
This example illustrates the preparation of 3-phenyl-3-cyano-8-benzyl-8azabicyclo[3.2.1 ]octane.
Sodium hydride (0.75g of a 55% suspension in oil) was carefully added to benzyl cyanide (0.69g) and meso-2.5-bis(chloromethyl)-1 -benzyipyrrolidine (l.Og) in Ν,Ν-dimethylformamide (30ml) at 0°C under nitrogen. The mixture was stirred at room temperature overnight and then poured into ice-cold water and extracted with diehloromethane. The aqueous layer was allowed to stand at room temperature overnight and then filtered and the solid residue washed with water and air dried. The solid product was chromatographed [SiO2; hexane:ethyl acetate (80:20)] to give a 10:1 (exo-phenyl): (endo-phenyl) mixture of 3-phenyl-3-cyano-8-benzyl-8-azabicyclo[3.2.1]octane (0.21g).
EXAMPLE 6
This example illustrates the preparation of exo- 3-(pvrid- 3-vI)-endo-3-cyano- 8-benzyl-8azabicyclo[3.2.1 ] octane.
Three drops of 5M hydrochloric acid was added to a stirred mixture of 2,5dimethoxytetrahydrofuran (16.5g) and water (70ml). After 10 minutes a mixture of benzylamine (13.6ml) and 5M hydrochloric acid (30ml) were added followed by the immediate addition of a mixture of 1,3-acetonedicarboxylic acid (18.2g) and sodium acetate (lOg) in water (100ml). After stirring at room temperature for 3 days, during which carbon dioxide was evolved, the mixture was
ΑΡ, Ο Ο 8 ο 3
- 21 haxified to ρΗ8 and extracted wi± ethyl acetate (x3). The combined extracts were dried (MgSO4) and evaporated under reduced pressure. Chromatography [SiCh; hexanerethyl acetate] to give 8benzyl-8-azabicyclo[3.2. l]octan-3-one (11.2g).
Potassium t-butoxide (2.5g) was added portionwise to a stirred mixture of 8-bcnzyl-85 azabicyclo[3.2.1]octan-3-one (2.0g), tosylmethyl isocyanide (2.36g) and ethanol (2ml) in dimethoxyethane (50ml) at 0°C under nitrogen. The mixture was stirred at 0°C for 0.5 hours and then overnight at room temperature:- The mixture was then filtered and the solid residue washed with dimethoxyethane. The combined filtrates were evaporated under reduced pressure and chromatographed [SiO^; hexanerethyl acetate (80:20)] to give 3-cyano-8-benzyl-810 azabicyclo[3.2.1]octane (0.87g).
j 3-Cyano-8-benzyl-8-azabicyclo[3.2.1]octane (0.5g) in tetrahydrofuran (2ml) was added dropwise to a stirred solution of lithium diisopropylamide [made by adding n-BuLi (1.5ml of a 1.6M solution in hexane) to diisopropylamine (0.246g) in tetrahydrofuran (2ml)] at -25°C under nitrogen. After 0.5 hours the mixture was cooled to -76°C and 3-fluoropyridine (0.215g) in tetrahydrofuran (2ml) was added. After 2 hours the mixture was allowed to warm room temperature overnight and • _ water then added. The mixture was then extracted with ethyl acetate (x3) and the combined extracts were washed with brine and water, dried (MgSO4) and evaporated under reduced pressure. Chromatography [SiO2; dichloromethane:methanol (95:5)] gave exo-3-(pyrid-3-yI)endo-3-cyano-8-benzyl-8-azabicyclo[3.2.1]octane (0.245g) which crystallised on standing m.p.
) 20 119-120°C.
: ·- ., EXAMPLE 7
This example illustrates the preparation of exo-3-(pvrid-3-vl)-endo-3-cyano-8-(2methoxyethyl)-8-azabicyclo[3.2.1 ]octane.
exo-3-(Pyrid-3-yl)-endo-3-cyano-8-azabicyclo[3.2.1]octane (0.30g), 2-bromoethyl methyl ether 25 (0.235g) and potassium carbonate (0.213g) were refluxed in ethanol (3ml) for 30 hours. The mixture was allowed to cool to room temperature, filtered and washed with ethanoL The filtrate was evaporated under reduced pressure and chromatographed [SiO2; dichloromethane:methanol (95:5)] to give exo-3-(pyrid-3-yl)-endo-3-cyano-8-(2-methoxvethy 1)-8azabicyclo[3.2.1]octane (0.223g).
EXAMPLE 8
This example illustrates the preparation of exo-3-(pyrid-2-yI)-endo-3-cyano-8-methyl-8azabicyclo[3.2.1 ]octane.
AP/P/ 9 7/01139 exo-3-Cyano-8-methyl-8-azabicyclo[3.2. ljoctane (0.5g) in tetrahydrofuran (3ml) was added to a solution of lithium diisopropylamide [made by adding n-BuLi (1.6ml of a 2.5M solution in hexane) to diisopropylamine (0.4g) in tetrahydrofuran (3ml)] at -25°C under nitrogen. After 30 minutes a solution of 2-fluoropyridine (0.388g) in tetrahydrofuran (3ml) was added.
After 1 hour the mixture was allowed to warm to room temperature and then stand overnight. Water was added and the mixture extracted with ethyl acetate (x3). The combined extracts were washed with water (x2), dried (MgSO4)-and evaporated under reduced pressure. Chromatography [SiO2; dichloromethane:methanol (90:10)] gave exo-3-(pvrid-2-yl)-endo-3cyano-8-methyl-8-azabicyclo[3.2.ljoctane (0.467g).
EXAMPLE 9
This example illustrates the preparation of exo-3-(pyrazin-2-yl)-endo-3-cyano-8-methyl-8azabicyclo[3.2. ljoctane.
exo-3-Cyano-8-methyl-8-azabicyclo[3.2. ljoctane (0.5g) in tetrahydrofuran (3ml) was added to a solution of lithium diisopropylamide [made by adding n-BuLi (1.6ml of a 2.5M solution in hexane) to diisopropylamine (0.4g) in tetrahydrofuran (3ml)j at -25°C under nitrogen. After 30 minutes the mixture was cooled to -78°C and a solution of chloropyrazine (0.46g) in tetrahydrofuran (5ml) was added. After 1 hour the mixture was allowed to warm to room temperature and stand overnight. Water was added and the mixture extracted with ethyl acetate (x3). The combined extracts were washed with brine and water, dried (MgSO4) and evaporated under reduced pressure. Chromatography [SiO2; dichloromethane:methanol (95:5) to (90:10)] gave exo-3-(pvrazin-2-yl)-endo-3-cyano-8-methyl-8-azabicyclo[3.2. ljoctane (0.368g) m.p. 76-77°C.
EXAMPLE 10
This example illustrates the preparation of exo-3-(6-chloropyrazin-2-yl)-endo-3-cyano-825 methyl-8-azabicyclo[3.2. ljoctane.
exo-3-Cyano-8-methyl-8-azabicyclo[3.2. ljoctane (l.Og) in tetrahydrofuran (5ml) was added to a solution of lithium diisopropylamide [made by adding n-BuLi (2.66ml of a 2.5M solution in hexane) to diisopropylamine (0.673g) in tetrahydrofuran (5ml)] at -25°C under nitrogen. After 30 minutes the mixture was cooled to -78°C and a solution of 2,6-dichloropyrazine (l.Og) in tetrahydrofuran (5ml) was added. After 1 hour the mixture was allowed to warm to room temperature and stand over the weekend. Water was added and the mixture extracted with ethyl acetate (x3). The combined extracts were washed with brine and water, dried
AP.0Q8Q 3
- 23 (MgSO4) and evaporated under reduced pressure. Chromatography [SiCE; dichloromethane:methanol (95:5)] gave exo-3-(6-chloropyrazin-2-yl)-endo-3-cyano-8-methyl8-azabicyclo[3.2.1]octane (1.10g) m.p. 79.8-80.1°C.
EXAMPLE 11
This example illustrates the preparation of exo-3-f6-chloropyridazin-3-vI)-endo-3-cyano-8methyl-8-azabicyclo[3.2.1 ]octane.
exo-3-Cyano-8-methyl-8-azabicyclo[3.2.1]octane (0.5g) in tetrahydrofuran (5ml) was added to a solution of lithium diisopropylamide [made by adding η-BuLi (1.4ml of a 2.5M solution in hexane) to diisopropylamine (0.45g) in tetrahydrofuran (2ml)] at -25°C under nitrogen.
After 30 minutes 1,3-dimethylimidazolidinone (1ml) was added and the mixture cooled to 78°C. A solution of 3,6-dichlorochloropyridazine (0.50g) in tetrahydrofuran (2ml) was added. After 2 hours the mixture was allowed to warm to room temperature and stand overnight. Water was added and the mixture extracted with ethyl acetate (x3). The combined extracts were washed with brine and water, dried (MgSO4) and evaporated under reduced pressure. Chromatography [SiCH; dichloromethane:methanol (95:5)] gave exo-3-(6chloropvridazin-3-vl)-endo-3-cyano-8-methyI-8-azabicycIo[3.2.1 ]octane (0.082g).
EXAMPLE 12
This example illustrates the preparation of exo-3-(5.6-dichloropyrid-3-yl)-endo-3-cyano-8methyl-8-azabicyclo[3.2.1 ]octane.
3-Chloro-2-hydroxy-5-nitropyridine (4.8g) was added to phosphorus oxychloride (11ml) and phosphorus pentachloride (4.45g) and the mixture refluxed overnight. The mixture was then cooled to room temperature and evaporated under reduced pressure. Iced water was added to the mixture and a solid product formed. The solid was removed by filtration, washed with water and air-dried to give 2,3-dichloro-5-nitropyridine (3.94g).
2,3-Dichloro-5-nitropyridine (3.9g) and iron powder (3.0g) were added to isopropyl alcohol (40ml) and water (8ml) and the mixture refluxed for 4 hours. The mixture was then cooled to room temperature and filtered (celite). The filtrate was evaporated under reduced pressure and chromatographed [SiO2; hexane:ethyl acetate (80:20) to (50:50)] to give 5-amino-2,3dichloropyridine (1.71 g).
5-Amino-2,3-dichloropyridine (0.80g) in dichioromethane (10ml) was added to boron trifluoride etherate (0.92ml) at -15°C under nitrogen. Dichioromethane (15ml) was added followed by t-butylnitrite (0.71ml) in dichioromethane (5ml). After 15 minutes the mixture
AP/P/ 9 7/01 139 was allowed to warm to -5°C over 20 minutes. Hexane was added and the resulting solid was filtered, air-dried and washed with ether and stored at approximately -20°C overnight. The solid was then heated until gas evolution had ceased and the product kugelrohr distilled to give 2,3-dichloro-5-fluoropyridine (0.104g).
exo-3-Cyano-8-methyl-8-azabicyclo[3.2.1]octane (0.10g) in tetrahydrofuran (lml) was added to a solution of lithium diisopropylamide [made by adding n-BuLi (0.29ml of a 2.5M solution in hexane) to diisopropylamine (0.073g) in tetrahydroiuran (lml)] at -25°C under nitrogen. After 30 minutes 2,3-dichloro-5-fluoropyridine (0.1 Og) in tetrahydrofuran (lml) was added. After 1 hour the mixture was allowed to warm to room temperature and stand overnight.
Water was added and the resulting mixture extracted with ethyl acetate (x3). The combined extracts were washed with water, dried (MgSOJ and evaporated under reduced pressure. Chromatography [SiCh; dichloromethane:methanol (95:5) to (90:10)] gave an orange gum which was triturated with hexane to give exo-3-(5,6-dichloropyrid-3-yl)-endo-3-cyano-8methyl-8-azabicyclo[3.2.1]octane (0.019g) as a yellow solid.
t>
EXAMPLE 13
This example illustrates the preparation of exo-3-(pyrid-3-yl~)-endo-3-cyano-8(methoxycarbonylmethyl)-8-azabicyclo[3.2.1 ]octane.
exo-3-(Pyrid-3-yl)-endo-3-cvano-8-azabicvcloi3.2.1'loctane (0.20g), ethyl bromoacetate (0.187g) and potassium carbonate (0.155g) were refluxed in ethanol (3ml) for 4 hours. The mixture was then filtered and the filtrate evaporated under reduced pressure. Chromatography [SiCL; dichloromethane-.methanol (95:5)] gave exo-3-(pyrid-3-yl)-endo-3-cyano-8(methoxycarbonylmethyl)-8-azabicyclo[3.2.1]octane (0.112g).
EXAMPLE 14
This example illustrates the preparation of exo-3-(pyrid-3-yl)-endo-3-cyano-825 (methylsulphonylmethylsulphonyI)-8-azabicyclo[3.2. ljoctane.
exp-3-(Pyrid-3-yI)-endo-3-cyano-8-azabicyclo[3.2.1]octane (0.39g) and triethylamine (15ml) were added to dichloromethane (5ml) and the mixture cooled to -20°C. Methane sulphonyl chloride (0.12ml) was added dropwise and the mixture allowed to warm to room temperature. After 1 hour the mixture was evaporated under reduced pressure and dissolved in ethyl acetate.
AP.00803
- 25 The resulting solution was washed with aqueous sodium bicarbonate solution and water (x2), dried (MgSO4) and evaporated under reduced pressure. Chromatography [SiCb; dichloromethanermethanol (90:10)] gave a gum which formed a solid on trituration with hexane and ether. Chromatography [SiO^; hexane:ethyl acetate (80:20)] gave exo-3-(pvrid-3-yl)-endo-35 cyano-8-(methylsulphonylmethylsulphonyl)-8-azabicyclo[3.2.1]octane (0.028g) m.p. 163164°C.
EXAMPLE 15This example illustrates the preparation of exo-3-(6-chloropvrid-3-yI)-endo-3-cyano-8methy l-8-azabicyclo[3.2.1 joctane.
exo-3-(Pvrid-3-vl)-endo-3-cvano-8-azabicyclor3.2.noctane (0.50g) in acetonitrile (3ml) was added dropwise to a stirred solution of di-t-butyl carbonate (0.512g) in acetonitrile (5ml) at 0°C. 4-Dimethylaminopyridine (0.02g) was added and after 30 minutes the mixture was wanned to room temperature, stirred for 2 hours and allowed to stand overnight. The mixture was evaporated under reduced pressure and chromatographed [SiO^; ethyl acetate:dichloromethane (20:80) to (30:70)] to give exo-3-(pyrid-3-yl)-endo-3-cyano-8-(tbutyloxycarbonyl)-8-azabicyclo[3.2. l]octane (0.602g).
m-Chloroperoxybenzoic acid (0.22g) was added to a solution of exo-3-(pvrid-3-vl)-endo-3cyano-8-(t-butyloxycarbonyl)-8-azabicyclo[3.2.1]octane (0.20g) in dichioromethane (2ml) at 20 0°C under nitrogen. After 1 hour the mixture was wanned to room temperature and allowed ff) to stand overnight. The mixture was evaporated under reduced pressure, dissolved in ethyl acetate, washed with aqueous sodium bicarbonate solution (x2), dried (MgSO4) and evaporated under reduced pressure to give exo-3-(N-oxopyrid-3-yl)-endo-3-cyano-8-(tbutyloxycarbonyl)-8-azabicyclo[3.2.1 ]octane (0.161 g).
exo-3-(N-oxopyrid-3-yl)-endo-3-cyano-8-(t-butyloxycarbonyl)-8-azabicyclo[3.2.1]octane (0.161g) was added to phosphorus oxychloride (1ml) and the mixture refluxed for 1 hour. The mixture was then allowed to cool to room temperature, evaporated under reduced pressure, toluene added and evaporated under reduced pressure. Ethyl acetate was added and the mixture washed with aqueous sodium hydroxide solution and water (x2), dried (MgSO4) and evaporated under reduced pressure to give exo-3-(6-chloropyrid-3-yl)-endo-3-cyano-8azabicyclo[3.2.1]octane (0.058g).
AP/PZ 9 7/01 139 exo-3-(6-Chloropyrid-3-vl)-endo-3-cyano-8-azabicyclor3.2.1 ]octane (O.O5g) and paraformaldehyde (0.50g) were added to formic acid (2ml) and the mixture heated under reflux. After 2 hours the mixture was allowed to cool to room temperature and stand overnight. The mixture was evaporated under reduced pressure and 2M sodium hydroxide added. The mixture was extracted with ethyl acetate (x3) and the combined extracts were washed with brine and water, dried (MgSO4), evaporated under reduced pressure and chromatographed [S1O2; dichloromethane:methanol (95:5)] to give exo-3-(6-chloropyrid-3-yI)endo-3-cyano-8-methyl-8-azabicyclo[3.2.1]octane (0.023g).
EXAMPLE 16
This example illustrates the preparation of exo-3-(5-chIoropvrid-3-vl)-endo-3-cyano-8-(nhexyl)-8-azabicyclo [3.2.1] octane.
exo-3-Cyano-8-methyl-8-azabicyclo[3.2.1]octane (0.5g) in tetrahydrofuran (3ml) was added to a solution of lithium diisopropylamide [made by adding η-BuLi (1.6ml of a 2.5M solution in hexane) to diisopropylamine (0.4g) in tetrahydrofuran (3ml)] at -25°C under nitrogen. After a further 15 minutes at -25°C 3,5-dichloropyridine (0.588g) in tetrahydrofuran (3ml) was added at -78°C. After 1 hour at the mixture was allowed to warm to room temperature and stand overnight. Water was then added and the resulting mixture extracted with ethyl acetate (x3). The combined extracts were washed with brine and water, dried (MgSO4) and evaporated under reduced pressure. Chromatography [SiO2; dichloromethane:methanol (90:10)] gave exo-3-(5-chloropyrid-3-yl)-endp-3-cyano-8-methyl-8-azabicyclo[3.2.1]octane (0.249g).
Vinyl chloroformate (2.6ml) in tetrahydrofuran (5ml) was added to a stirred solution of exo3-(5-chloropyrid-3-yl)-endo-3-cyano-8-methyl-8-azabicyclo[3.2.1]octane (2.6g) in tetrahydrofuran (25ml) at 0°C. The mixture was allowed to warm to room temperature over 1 hour, refluxed for 2 hours and then allowed to cool to room temperature. After 20 hours the mixture was partitioned between water and ethyl acetate and the organic layer was separated, washed with water and dried (MgSO4). Evaporation under reduced pressure gave exo-3-(5-chloropyrid-3-yl)-endo-3-cyano-8-(vinyloxycarbonyl)-8-azabicyclo[3.2.1 ]octane (2.0g).
exo-3-(5-Chloropyrid-3-yl)-endo-3-cyano-8-(vinyloxycarbonyl)-8-azabicyclo[3.2.1]octane (2.6g) was dissolved in methanol (50ml) and concentrated hydrochloric acid (7ml) added.
The mixture was refluxed for 3 hours after which the mixture was evaporated under reduced
ΑΡ- 00803
- 27 pressure and basified with aqueous sodium carbonate. The resulting mixture was extracted with ethyl acetate and evaporated under reduced pressure to give a brown solid. This was then washed with hexane to give exo-3-(5-chloropyrid-3-vI)-endo-3-cyano-8azabicyclo[3.2. ljoctane (1.2g).
n-Hexyl bromide (0.1ml) and potassium carbonate (O.lg) were added to ex0-3-(5chloropyrid-3-yl)-endo-3-cyano-8-azabicyclo[3.2. ljoctane (0.15g) in ethanol (2ml) and the mixture refluxed for 44 hours. The mixture was then diluted with ethanol, filtered and evaporated under reduced pressure. Chromatography [SiO2; dichloromethane-.methanol (96:4)] gave exo-3-(5-chloropyrid-3-yl)-endo-3-cyano-8-(n-hexyl)-8-azabicyclo[3.2.ljoctane
.. 10 (0.123g).
-J EXAMPLE 17
This example illustrates the preparation of exo-3-(5-chloropyrid-3-yl)-endo-3-cyano-8-aIlyl-8azabicyclo[3.2.1 ]octane.
Allyl bromide (62μ1) and potassium carbonate (O.lg) were added to exo-3-(5-chloropyrid-315 yl)-endo-3-cyano-8-azabicyclo[3.2. ljoctane (0.15g) in ethanol (2ml) and the mixture stirred for 3 hours and then allowed to stand overnight. The mixture was then diluted with ethanol, filtered and evaporated under reduced pressure. Chromatography [SiO2; dichloromethane-.methanol (95:5)] gave exo-3-(5-chloropvrid-3-vl)-endo-3-cvano-8-allyl-8azabicyclo[3.2.ljoctane (0.167g).
? 20 EXAMPLE 18
This example illustrates the preparation of exo-3-(5-chloropyrid-3-yl)-endo-3-cyano-8-(2,2,2trifluoroethyl)-8-azabicyclo[3.2.1 ]octane.
A few drops of dilute hydrochloric acid were added to a solution of 2,5dimethoxytetrahydrofuran (16.5g) in water (70ml). After stirring at room temperature for 30 minutes 2,2,2-trifluoroethylamine hydrochloride (16.9g), 1,3-acetonedicarboxylic acid (18.3g) and sodium acetate (lO.Og) were added and the mixture stirred at room temperature for 2 days. The mixture was diluted to 500ml with water, saturated with potassium carbonate and extracted with ethyl acetate (x2). The combined organic extracts were washed with aqueous potassium carbonate, dried (MgSO4) and evaporated under reduced pressure. Distillation (90°C; O.lmmHg) gave 8-(2,2,2-triflu0roethyl)-8-azabicyclo[3.2.1]octan-3-one (8.7g).
Potassium t-butoxide (5.4g) was added slowly with cooling to a stirred solution of 8-(2,2,2trifluoroethyl)-8-azabicyclo[3.2.1]octan-3-one (4.0g) and tosylmethyl isocyanide (4.9g) in
AP/P/ 97/01 139 dimethoxyethane (80ml) and ethanol (5ml) under nitrogen at such a rate so as to keep the temperature below 10°C. The mixture was stirred for 18 hours while allowing it to warm to room temperature, evaporated under reduced pressure and added to aqueous potassium carbonate solution. The mixture was extracted with ethyl acetate (x2) and the combined extracts were dried (MgSO4) and evaporated under reduced pressure to give an oil. The mixture was extracted with refluxing hexane and the extracts allowed to cool and evaporated under reduced pressure to give- e2co-3-cyano-8-(2,2,2-trifluoroethyl)-8azabicyclo[3.2.1]octane (2.5g) m.p. 90-92°C.
exo-3-Cyano-8-(2,2,2-trifluoroethyl)-8-azabicyclo[3.2.1]octane (1.09g) in tetrahydrofuran (10ml) was added to a stirred solution of lithium diisopropylamide [made by adding n-BuLi (2.4ml of a 2.5M solution in hexane) to diisopropylamine (0.61g) in tetrahydrofuran (10ml)] at -25°C under nitrogen. After 2 hours at -25°C the mixture was cooled to -76°C and 3,5dichloropyridine (0.74g) in tetrahydrofuran (10ml) added. The mixture was allowed to warm to room temperature, stirred for 18 hours and evaporated under reduced pressure. The mixture was dissolved in ether, washed with water (x2), dried (MgSO4) and evaporated under t
reduced pressure. Chromatography [SiO2; diethyl ethenhexane (20:80) to (50:50)] gave exo3-(5-chloropyrid-3-yl)-endp-3-cyano-8-(2,2,2-trifluoroethyl)-8-azahicyclo[3.2.1]octane (0.45g) m.p. 109.5-111.5°C.
EXAMPLE 19
This example illustrates the preparation of exo-3-(5-bromopyrid-3-yl)-endo-3-cyano-8methyl-8-azabicyclo[3.2. l]octane.
exo-3-Cyano-8-methyl-8-azabicyc!o[3.2.1]octane (0.5g) in tetrahydrofuran (3ml) was added to a solution of lithium diisopropylamide [made by adding n-BuLi (1.6ml of a 2.5M solution in hexane) to diisopropylamine (0.4g) in tetrahydrofuran (3ml)] at -25°C under nitrogen. After 30 minutes the mixture was cooled to -76°C and a solution of 3,5-dibromopyridine (0.94g) in tetrahydrofuran (3ml) added. After 1 hour the mixture was allowed to warm to room temperature and left to stand overnight. Water was added and the resulting mixture extracted with ethyl acetate (x3). The combined extracts were washed with brine (x2) and water, dried (MgSO4) and evaporated under reduced pressure. Chromatography [SiO2; dichloromethane:methanol (90:10)] gave exo-3-(5-bromopyrid-3-yl)-endo-3-cyano-8-methyl8-azabicyclo[3.2.1]octane (0.327g) m.p. 144-145°C.
AP. Ο ο β o 3
- 29 EXAMPLE 20 •JO '15
This example illustrates the preparation of exo-3-(5-cyanopyrid-3-yl)-endo-3-cyano-8-methyl8-azabicyclo[3.2.1 ]octane.
exp-3-(5-Bromopyrid-3-yl)-endp-3-cyano-8-methyl-8-azabicyclo[3.2.1 Joctane (0.30g) and copper(I) cyanide (0.345g) were heated at 200°C in N-methylpyirolidinone (10ml) under nitrogen. After 36 hours the reaction was allowed to cool to room temperature and water was added followed by aqueous ammonium hydroxide solution (density=0.88). The mixture was extracted with ethyl acetate (x3) and the combined extracts were washed with brine and water, dried (MgSCU) and evaporated under reduced pressure. The resulting oil was dissolved in ether and washed with brine (x7), dried (MgSO4) and evaporated under reduced pressure. Chromatography [S1O2·, dichloromethane:methanol (95:5)] gave a yellow solid. This was recrystallised three times (from dichloromethane/hexane, ethyl acetate/hexane and dichloromethane/hexane) to give exo-3-f5-cyanopyrid-3-yl)-endo-3-cyano-8-methvl-8azabicyclo[3.2.1]octane (0.49g) m.p. 183.5-184°C.
EXAMPLE 21
This example illustrates the preparation of exo-3-(5-ethoxypyrid- 3-yl)-endo-3-cyano-8methyl-8-azabicyclo[3.2.1 Joctane.
exo-3-( 5-Chloropyrid-3-yl)-endo-3-cyano-8-methvl-8-azabicyclor3.2.1 loctane (0.30g) and 20 sodium ethoxide (0.625g) were heated at 80°C in Ν,Ν-dimethylformamide (10ml) under nitrogen. After 5 hours the mixture was allowed to cool to room temperature and water added. The mixture was extracted with ethyl acetate (x3) and the combined extracts were washed with brine (x2) and water, dried (MgSO4) and evaporated under reduced pressure.
Chromatography [SiCh; dichloromethane:methanol (90:10)] gave an oil. A small amount of 25 hexane was added and the mixture was allowed to stand at approximately 0°C overnight after which a solid product had formed. The mixture was filtered and the solid washed with a small amount of hexane to give exp-3-(5-ethoxypyrid-3-yl)-endp-3-cyano-8-methyl-8azabicyclo[3.2.1]octane (O.lO5g) m.p. 56-57°C.
EXAMPLE 22
This example illustrates the preparation of exo-3-(5-ch!oropyrid-3-yI)-endo-3-cyano-8isopropyl-8-azabicyclo[3.2.1 )octane.
AP/P/ 9 7/01 139 ·? J.
2M Hydrochloric acid (8 drops) was added to a stirred solution of 2,5dimethoxytetrahydrofuran (16.5g) in water (70ml). After 15 minutes a mixture of diisopropylamine (7.38g) and 2M hydrochloric acid (40ml) was added to the reaction followed by acetonedicarboxylic acid (18.25g) and sodium acetate (lO.Og) in water (100ml). After 3 days 1,3-acetonedicarboxylic acid (6.0g) and sodium acetate (3.0g) were added. After a further 6 days the mixture was basified to pH8 and extracted with ethyl acetate. The extracts were dried (MgSO4) and evaporated under reduced pressure. The aqueous fraction was then extracted with chloroform and the extracts dried (MgSO4) and evaporated under reduced pressure. Distillation of the combined extracts (95-115°C; 18mmHg) gave 8isopropyl-8-azabicyclo[3.2.1]octan-3-one (3.37g).
Potassium t-butoxide (5.0g) was added slowly with cooling to a stirred solution of 8isopropyl-8-azabicyclo[3.2.1]octan-3-one (3.16g) and tosylmethyl isocyanide (4.80g) in dimethoxyethane (50ml) and ethanol (2.2ml) under nitrogen at such a rate so as to keep the temperature below 10°C. After 1 day tosylmethyl isocyanide (l.Og), potassium t-butoxide (l.Og) and ethanol (1ml) were added. After a further day the mixture was filtered and the filtrate evaporated under reduced pressure and chromatographed [SiO2; dichloromethanermethanol (95:5)] to give exo-3-cyano-8-isopropyl-8-azabicyclo[3.2.1]octane (0.90g).
Lithium bis(trimethylsilyl)amide (2.5ml of a 1M solution in tetrahydrofuran) in tetrahydrofuran (5ml) was added to a stirred solution of exo-3-cvano-8-isopropyl-8azabicyclo[3.2.1]octane (0.38g) and 3,5-dichloropyridine (0.34g) in tetrahydrofuran (5ml) at 10°C over 30 minutes. The mixture was then stirred at room temperature for 2 hours and allowed to stand at room temperature overnight. 3,5-Dichloropyridine (0.15g) was added followed by lithium bis(trimethylsilyl)amide (1.0ml of a 1M solution in tetrahydrofuran) over 30 minutes. After 2 hours lithium bis(trimethylsilyl)amide (1.0ml of a 1M solution in tetrahydrofuran) was added dropwise and after a further 1 hour additional lithium bis(trimethylsilyl)amide (1.0ml of a 1M solution in tetrahydrofuran) was added and the mixture warmed to 50°C. After 5 minutes the reaction was cooled to room temperature and aqueous sodium carbonate solution added. The mixture was extracted with ethyl acetate (x2) and the combined extracts washed with brine, dried (MgSO4) and evaporated under reduced pressure to give a brown oil. The oil was extracted with boiling hexane arid the combined
ΑΡ.00803
- 31 extracts evaporated under reduced pressure to give exo-3-(5-chloropyrid-3-vB-endo-3-cyan(>8-isopropyl-8-azabicyclo[3.2. l]octane (0.60g).
EXAMPLE 23
This example illustrates the preparation of exo-3-f2.6-dichloropyrimid-4-yl)-endo-3-cyano-85 methyl-8-azabicyclo[3.2.1]octane.
exo-3-Cyano-8-methyl-8-azabicyclo[3.2.1]octane (0.5g) in tetrahydrofuran (3ml) was added to a solution of lithium diisopropyiamide [made by adding n-BuLi (1.6ml of a 2.5M solution in hexane) to diisopropylamine (0.4g) in tetrahydrofuran (3ml)] at -25°C under nitrogen. After 30 minutes the mixture was cooled to -78°C and a solution of 2,4,6-trichloropyrimidine (0.728g) in tetrahydrofuran (5ml) was added. After 1 hour the mixture was allowed to warm to room temperature, stirred for 2 hours and allowed to stand overnight. Water was added and the mixture extracted with ethyl acetate (x3). The combined extracts were washed with brine and water, dried (MgSO4) and evaporated under reduced pressure. Chromatography [SiCh; dichloromethane:methanol (95:5) to (90:10)] gave exo-3-(2.6-dichloropyrimid-4-yl)15 endo-3-cyano-8-methyl-8-azabicyclo[3.2.1]octane (0.087g) m.p. 95-97°C.
EXAMPLE 24
Ζ»1'
This example illustrates the preparation of exo-3-(2-chloropyrid-4-yl)-endo-3-cyano-8methyl-8-azabicyclo[3.2.1 ]octane.
exo-3-Cyano-8-methyl-8-azabicyclo[3.2.1]octane (0.5g) in tetrahydrofuran (3ml) was added to a solution of lithium diisopropyiamide [made by adding n-BuLi (1.6ml of a 2.5M solution in hexane) to diisopropylamine (0.4g) in tetrahydrofuran (3ml)] at -25°C under nitrogen. /After 30 minutes the mixture was cooled to -7 8 °C and a solution of 2,4,6-trichloropyridine (0.724g) in tetrahydrofuran (5ml) was added. After 1 hour the mixture was allowed to warm to room temperature and allowed to stand overnight. Water was added and the mixture extracted with ethyl acetate (x3). The combined extracts were dried (MgSO4) and evaporated under reduced pressure. Chromatography [SiO2; dichloromethane:methanol (95:5)] gave a solid product which was recrystallised (ethyl acetate/hexane) to give exo-3-(2.6dichloropyrid-4-yl)-endo-3-cyano-8-methyl-8-azabicyclo[3.2.1]octane (0.389g) m.p. 165166°C.
AP/PZ 9 7/01 139 exo-3-(2.6-Dichloropyrid-4-yl)-endo-3-cvano-8-methyl-8-azabicyclo[3.2.1]octane (0.50g) and hydrazine hydrate (0.106ml) were refluxed in isopropyl alcohol (5ml) for 5 hours and then left to stand overnight Hydrazine hydrate (0.106ml) was added and the mixture refluxed
- * *·
- 32 for 8 hours. More hydrazine hydrate (0.106ml) was added and the mixture refluxed for a further 8 hours. After cooling to room temperature the mixture was evaporated under reduced pressure and the residue extracted with dichloromethane. The extracts washed with water (x2), dried (MgSO4), evaporated under reduced pressure and triturated with hexane and ether to give exo-3-(2-chloro-6-hydrazinopyrid-4-yl)-endo-3-cyano-8-methyl-8azabicyclo[3.2.1]octane (0.205g) m.p. 215-216°C.
Copper(H) sulphate octahydrate (0.36g) was added to a solution of exo-3-(2-chloro-6hydrazinopyrid-4-yl)-endo-3-cyano-8-methyl-8-azabicyclo[3.2.1]octane (0.170g) in water (3ml) and the mixture refluxed for 7 hours. After cooling to room temperature ammonium hydroxide solution (density=0.88) was added and the mixture extracted with ethyl acetate (x3). The combined extracts were washed with brine and water, dried (MgSO4) and evaporated under reduced pressure. Chromatography [S1O2; dichloromethane:methanol (90:10)] gave exo-3-(2-chloropyrid-4-yl)-endo-3-cyano-8-methyl-8-azabicyclo[3.2.1]octane (0.052g) m.p. 104-105°C.
EXAMPLE 25 t
This example illustrates the preparation of exo-3-(pyrid-4-yl)-endo-3-cvano-8-methyl-8azabicyclo[3.2.1 ]octane.
exo-3-(2,6-Dichloropyrid-4-yl)-endo-3-cyano-8-methyl-8-azabicyclo[3.2.1]octane (0.35g), crushed potassium hydroxide (0.133g) and palladium on charcoal (0.20g) were stirred in methanol (10ml) under hydrogen for 3 hours and then allowed to stand for 3 days. The mixture was filtered (celite), evaporated under reduced pressure and dissolved in ethyl acetate. The resulting solution was washed with aqueous sodium hydroxide and water, dried (MgSO4) and evaporated under reduced pressure to give a solid product which was washed with hexane and ether to give exo-3-(pyrid-4-yD-endo-3-cvano-8-methyl-8azabicyclo[3.2.1]octane (0.072g) m.p. 74.5-76°C.
EXAMPLE 26
This example illustrates the preparation of exo-3-(5-chloropyrid-3-yl)-endo-3-cyano-8-(3.3difluoroprop-2-en-1 -yl)-8-azabicyclo[3.2.1 ]octane.
exo-3-(5-Chloropyrid-3-yl)-endo-3-cyano-8-azabicycloi3.2.1]octane (0.248g), l-bromo-1,1difluoroprop-2-ene (0.314g) and potassium carbonate (0.345g) were stirred in ethanol (2ml) for 2 hours and then allowed to stand for 4 days. The mixture was then evaporated under reduced pressure and water added. The mixture was then extracted with dichloromethane
AP.00803
- 33 (x3) and the combined extracts were washed with brine, dried (MgSO4) and evaporated under reduced pressure. Filtration [SiO2; dichloromethane:methanol (98:2)] gave exo-3-(5chloropyrid-3-yl)-endo-3-cyano-8-(3,3-difluoroprop-2-en-l-yl)-8-azabicyclo[3.2.1]octane (0.287g).
EXAMPLE 27
This example illustrates the preparation of exo-3-(5-chloropyrid-3-yI)-endo-3-cyanO-8-(3oxo-4,4,4-trifluorobut-1 -en- i-yl)-8-azabicyclo[3.2.1 ]octane.
S2co-3-(5-Chloropyrid-3-yl)-endo-3-cyano-8-azabicyclo[3.2.1 ]octane (0.30g), 4-ethoxy-1,1,1trifluorobut-3-en-2-one (0.204g) and potassium carbonate (0.20g) were heated under reflux 10 in ethanol. After 4 hours the mixture was allowed to cool to room temperature and water added. The mixture was extracted with ethyl acetate (x3) and the combined extracts were washed with brine (x2) and water, dried (MgSO4) and evaporated under reduced pressure. Chromatography [SiO2; dichloromethanermethanol (95:5)] gave exo-3-(5-chloropyrid-3-yl)endo-3-cyano-8-(3-oxo-4.4.4-trifluorobut-1 -en-1 -yl)-8-azabicyclo[3.2.1 ]octane (0.162g) m.p. 15 144-145°C.
EXAMPLE 28
This example illustrates the preparation of exo-3-(5-chloropyrid-3-yI)-endo-3-cyano-8-acetyl8-azabicyclo[3.2.1 ]octane.
Ν,Ν-Diisopropylethylamine (0.43ml) and acetyl chloride (0.18ml) were added to exo-3-(520 chloropyrid-3-yl)-endo-3-cyano-8-azabicyclo[3.2.1]octane (0.50g) in dichloromethane (10ml) at room temperature. After 10 minutes the mixture was evaporated under reduced pressure and ethyl acetate (50ml) added. The resulting mixture was washed with potassium carbonate solution, dried (MgSO4) and evaporated under reduced pressure. The resulting product was triturated with hot hexane and evaporated under reduced pressure to give exo-3-(525 chloropyrid-3-yl)-endo-3-cyano-8-acetyl-8-azabicyclo[3.2.1]octane (0.43g) m.p. 162-165°C. EXAMPLE 29
This example illustrates the preparation of exo-3-(5-chloropyrid-3-yl)-endo-3-cyano-8azabicyclo[3.2.1 ]octane hydroperchlorate.
Perchloric acid (1.19ml) was added dropwise to a stirred suspension of exo-3-(5-chloropyrid30 3-yl)-endo-3-cyano-8-azabicyclo[3.2.1]octane (5.0g) in diethyl ether (100ml) at room temperature. After 5 hours the mixture was filtered and the precipitate washed with diethyl
AP/P/ 9 7/01139 ether to give exo-3-(5-chloropyrid-3-yl)-endp-3-cyano-8-azabicyclo[3.2.1]octane hydroperchlorate (5.36g).
EXAMPLE 30
This example illustrates the preparation of exo-3-f5-chloropyrid-3-yl)-endo-3-cyano-8-(tert5 butyl)-8-azabicyclo[3.2.1 joctane.
Acetone (0.42ml) was added to a stirred solution of exo-3-(5-chloropyrid-3-yl)-endo-3cyano-8-azabicyclo[3.2.1]octane hydroperchlorate (LOg) in ethanol (2rnl) at room temperature under nitrogen. After 30 minutes the mixture was heated to 50°C. After 1 hour the mixture was evaporated under reduced pressure. Acetone was then added and the mixture heated under reflux for 3 hours and then evaporated under reduced pressure. Diethyl ether (10ml) was added followed by methylmagnesium bromide (4.3ml of a 3.0M solution in diethyl ether). The mixture was‘then heated under reflux for 6 hours and then allowed to stand at room temperature overnight. Saturated ammonium chloride solution was then added and the mixture extracted with dichloromethane (x3). The combined extracts were washed with brine, dried (MgSO4) and evaporated under reduced pressure. Chromatography [S1O2; dichloromethane:methanol (95:5)] gave exo-3-(5-chioropyrid-3-yI)-endo-3-cyano-8-(tertbutyl)-8-azabicyclo[3.2.1 joctane (0.218g) m.p. 127-129°C.
EXAMPLE 31
This example illustrates the preparation of exo-3-(5-chloropyrid-3-yl)-endo-3-cyano-8-(220 phenyl-3-oxo-prop-2-yl)-8-azabicyclo[3.2.1 joctane.
2-Phenylpropanal (1.08g) was added to a mixture of exo-3-(5-chloropyrid-3-yl)-endo-3cyano-8-azabicyclo[3.2.1 joctane (2.0g) and p-toluenesulphonic acid (0.15g) in toluene (30ml) and the mixture heated under Dean and Stark reflux for 3 hours. After standing at room temperature overnight the mixture was evaporated under reduced pressure to give exo-3-(525 chloropyrid-3-y l)-endo-3-cyano-8-(2-phenylprop-1 -en-1 -yl)-8-azabicyclo[3.2.1 joctane which was used without further purification.
Sodium N-chloro-p-toluenesulphonamide (2.3g) was added to the exo-3-(5-chloropyrid-3-yl)endo-3-cyano-8-(2-phenylprop-l-en-l-yl)-8-azabicyclo[3.2.1joctane from the above reaction in dichloromethane (30ml) and the mixture stirred at room temperature for 5 hours. After standing at room temperature over the weekend the mixture was stirred for 8 hours and then allowed to stand overnight. The mixture was then filtered (celite) and the residue washed with dichloromethane. The combined filtrates were washed with sodium hypochlorite (x2)
AP.ο Ο 8 Ο 3
- 35 and brine, dried (MgSO4) and evaporated under reduced pressure. Chromatography [SiO2; dichloromethane:methanol (98:2)] followed by chromatography [SiO2; dichioromethane: methanol (99:1)] gave exo-3-(5-chloropyrid-3-vl)-endo-3-cyano-8-f2phenyl-3-oxo-prop-2-yl)-8-azabicyclo[3.2.1]octane (0.43g) m.p. 124-126°C.
EXAMPLE 32
This example illustrates the preparation of exo-3-(5-chloropyrid-3-yl)-endo-3-cyano-8-(2phenylbut-3-en-2-yl)-8-azabicyclo[3.2.1 ]octane. Sodium methoxide (0.085g) was added in two portions to a stirred solution of methyltriphenylphosphonium bromide (0.56g) in dimethyl sulphoxide (30ml) at room temperature under nitrogen. The mixture was warmed to 70°C and after 2 hours exo-3-(5chloropyrid-3-yl)-endo-3-cyano-8-(2-phenyl-3-oxo-prop-2-yl)-8-azabicyclo[3.2.1 ]octane (0.30g) in a small volume of dimethyl sulphoxide was added dropwise. After 3 hours the mixture was allowed to cool to room temperature and stand overnight. The mixture was poured into ice/water and the resulting mixture extracted with ethyl acetate (x3). The combined extracts were washed with brine (x2), dried (MgSO4) and evaporated under reduced pressure. Chromatography [SiO2; ethyl acetate:hexane (90:10)] gave exo-3-(5chloropyrid-3-yl)-endo-3-cyano-8-(2-phenylbut-3-en-2-yl)-8-azabicyclo[3.2.1]octanc (0.24g).
EXAMPLE 33
This example illustrates the preparation of exo-3-(5-chioropyrid-3-yl)-endo-3-cyano-8-(220 phenyl-3-hydroxyprop-2-yl)-8-azabicyclo[3.2. l]octane.
Sodium borohydride (0.094g) was added to a stirred solution of exo-3-i5-chioropvrid-3-yl)endo-3-cyano-8-(2-phenyl-3-oxo-prop-2-yl)-8-azabicyclo[3.2.1]octane (0.90g) in ethanol (15ml) under nitrogen. After 2 hours the mixture was poured into brine and the resulting mixture extracted with ethyl acetate (x2). The combined extracts were dried (MgSCL), evaporated under reduced pressure and chromatographed [SiO2; ethyl acetate:hexane (50:50)] to give exo-3-(5-chloropyrid-3-yl)-endo-3-cyano-8-f2-phenvl-3-hvdroxyprop-2-vl)-8azabicyclo[3.2.1]octane (0.777g) m.p. 124-126°C.
EXAMPLE 34
This example illustrates the preparation of exo-3-(5-chloropyrid-3-vl)-endo-3-cyano-8-(230 fluoro-2-phenylprop-l-yl)-8-azabicyclo[3.2.1]octane.
Diethylaminosulphur trifluoride (0.4ml) and exo-3-(5-chloropvrid-3-yl)-endo-3-cvano-8-(2phenyl-3-hydroxyprop-2-yl)-8-azabicyclo[3.2.1]octane (0.10g) were stirred in
AP/P/ 9 7/01139 dichloromethane (0.2ml) at room temperature for 4 hours. The mixture was allowed to stand at room temperature over the weekend and water added. The mixture was extracted with ethyl acetate and the aqueous layer basified with saturated sodium bicarbonate solution. The aqueous layer was then extracted with ethyl acetate (x3) and the combined organic extracts were washed with sodium bicarbonate solution and brine, dried (MgSO4) and evaporated under reduced pressure. Chromatography [SiO2; e±yl acetate:hexane (17:83)] gave exo-3(5-chloropyrid-3-yl)-endo-3-cyano-8-(2-fluoro-2-phenylprop-l-yl)-8-azabicyclo[3.2.1]octane (0.075g).
EXAMPLE 35
This example illustrates the preparation of exo-3-(5-chloropvrid-3-yI)-endo-3-cyano-8-(2phenyl-3-acetoxyprop-2-yl)-8-azabicyclo[3.2.1]octane.
Triethylamine (0.06ml) and acetyl chloride (0.029ml) were added to a stirred solution of exo3-(5-chloropyrid-3-yl)-endo-3-cyano-8-(2-phenyl-3-hydroxyprop-2-yl)-8azabicyclo[3.2.1]octane (0.15g) in dichloromethane (5ml) at room temperature under nitrogen. After 1.5 hours dichloromethane was added and the mixture washed with water (x2) and brine, dried (MgSO4) and evaporated under reduced pressure. Chromatography [SiO2; ethyl acetate:hexane (20:80)] gave exo-3-(5-chloropyrid-3-vl)-endo-3-cyano-8-(2phenyl-3-acetoxyprop-2-yl)-8-azabicyclo[3.2.1]octane (0.14g) m.p. 130-131°C.
EXAMPLE 36
This example illustrates the preparation of exo-3-(5-chloropyrid-3-yl)-endo-3-cyano-8formyl-8-azabicyclo[3.2. l]octane.
exo-3-(5-Chloropyrid-3-ylTendo-3-cyano-8-azabicycloi 3.2.1 loctane (3.0g) and formic acid (1.14ml) were heated at reflux for 4 hours. The mixture was then heated at 110°C overnight and formic acid (1.0ml) added. After 8 hours the mixture was allowed to cool to room temperature and stand overnight. Ethyl acetate was added and the mixture washed with 2M sodium hydroxide solution (x2), water and brine, dried (MgSO4) and evaporated under reduced pressure. Chromatography [SiO2; ethyl acetate-.methanol (95:5)] gave exo-3-(5chloropyrid-3-yl)-endo-3-cyano-8-formyl-8-azabicyclo[3.2.1]octane (1.675g) m.p. 141142°C.
EXAMPLE 37
This example illustrates the preparation of exo-3-(5-chloropvrid-3-vll-endo-3-cyano-8(diisopropylcarbamyl)-8-azabicyclo[3.2.1]octane.
AP.00803
- 37 Triethylamine (0.27ml) followed by diisopropylcarbamyl chloride (0.317g) was added to a stirred solution of exo-3-(5-chloropyrid-3-yl)-endo-3-cyano-8-azabicyclo[3.2.1]octane (0.40g) in dichioromethane (5ml) at room temperature. After 2 hours the mixture was allowed to stand at room temperature for 4 days. Dichioromethane was then added and the mixture washed with water (x2) and brine, dried (MgSO4) and evaporated under reduced pressure. Filtration [SiO2; ethyl acetate] gave exo-3-(5-chloropvrid-3-yi)-endo-3-cyano-8(diisopropylcarbamyl)-8-azabicyclo[3.2.1]octane (0.12g) m.p. 118-121°C.
EXAMPLE 38
This example illustrates the preparation of exo-3-(5-chloropyrid-3-yl)-endo-3-cyano-8-(tert.-,. 10 butylcarbamyl)-8-azabicyclo[3.2.1]octane.
•A
Triethylamine (0.27ml) followed by tert-butylisocyanate (0.22ml) was added to a stirred solution of exo-3-f5-chloropyrid-3-yl)-endo-3-cyano-8-azabicyclor3.2.11octane (0.40g) in dichioromethane (4ml) at room temperature. After 3 hours the mixture was allowed to stand at room temperature overnight and dichioromethane then added. The mixture was then washed with water (x2) and brine, dried (MgSO4) and evaporated under reduced pressure. Chromatography [SiO2; diethyl ether] gave exo-3-(5-chloropyrid-3-yl)-endo-3-cyano-8-(tertbutylcarbamyI)-8-azabicycio[3.2.1]octane (0.40g) m.p. 62-65°C.
EXAMPLE 39
This example illustrates the preparation of (R)-exo-3-f5-chloropyrid-3-yl)-endo-3-cyano-8-f 1 z 20 phenylethyl)-8-azabicyclo[3.2.1]octane.
) Three drops of 5M hydrochloric acid were added to a mixture of 2,5dimethoxytetrahydrofuran (I6.5g) and water (70ml). A cooled mixture of (R)-amethylbenzyiamine (15.125g) and 5M hydrochloric acid (30ml) was then added followed by 1,3-acctonedicarboxylic acid (18.26g) sodium acetate (lOg) and water (100ml). After 5 days the mixture was basified with aqueous sodium carbonate solution and extracted with ethyl acetate. The extracts were washed with brine, dried (MgSO4) and evaporated under reduced pressure. Chromatography [SiO2; ethyl acetate:hexane (10:90) to (20:80)] gave (R)-8-(lphenylethyl)-8-azabicyclo[3.2.1 ]octan-3-one.
Potassium t-butoxide (13.4g) was added portionwise to a stirred mixture of gave (R)-8-(l30 phenylethyl)-8-azabicyclo[3.2.1]octan-3-one (11.45g) and tosylmethyl isocyanide (12.7g) in dimethoxyethane (200ml) and ethanol (6ml) at -5 °C at such a rate to maintain the temperature below -2°C. After stirring overnight the mixture was filtered (celite) and the filtrate evaporated
AP/P/ 9 7 /01139 under reduced pressure. The residue was then dissolved in ethyl acetate, washed with water, dried (MgSO4) and evaporated under reduced pressure. Chromatography [SiO2; ethyl acetate:hexane (50:50)] gave (R)-exo-3-cyano-8-(l-phenylethyl)-8-azabicyclo[3.2.1]octane (3.5g) m.p. 138139.5°C.
Lithium bis(trimethylsilyl)amide (4.8ml of a 1.0M solution in tetrahydrofuran) v/as added to a stirred solution of (R)-exo-3-cyan 0-8-( 1 -phenvlethyI)-8-azabicvclof3.2.1 loctane (l.Og) and
3,5-dichloropyridine (0.674g) in tetrahydrofuran (20ml) at 0°C under nitrogen. The mixture was allowed to warm to room temperature and stand for 24 hours. Water (20ml) was added and the mixture stirred for 30 minutes and then allowed to stand for 2 days. The mixture was extracted with ethyl acetate and the extracts washed with brine, dried (MgSO4) and evaporated under reduced pressure. Chromatography [SiO2; ethyl acetate-.hexane (50:50)], preparative thin layer chromatography [SiO2; ethyl acetate:hexane (25:75)] and recrystallisation from hexane gave (R)-exo-3-(5-chloropyrid-3-yl)-endo-3-cyano-8-(lphenylethyl)-8-azabicyclo[3.2.1 Joctane (0.46g) m.p. 113-115°C.
EXAMPLE 40
This example illustrates the preparation of exo-3-(5-aminopyrid-3-yI)-endo-3-cyano-8methyl-8-azabicyclo[3.2.1 Joctane.
Ammonia solution (35%) was added to exo-3-(5-bromopyrid-3-yl)-endo-3-cyano-8-methyl-8azabicyclo[3.2.1 Joctane (0.106g) and copper(II) sulphate hydrate (O.OOlg) and the tube sealed. The mixture was heated at 100°C for 20 hours and then 150°C for 24 hours. The mixture was then cooled and evaporated under reduced pressure. The residue was then dissolved in methanol, charcoal added and the mixture filtered and evaporated under reduced pressure. Water and dichioromethane were added followed by ammonia solution and the resulting mixture was extracted with dichioromethane. The combined extracts were washed with brine, dried (MgSO4) and evaporated under reduced pressure to give exo-3-f5aminopvrid-3-yl)-endo-3-cyano-8-methyl-8-azabicyclo[3.2.1 loctane (0.045g) m.p. 188190°C.
EXAMPLE 41
This example illustrates the preparation of exo-3-(5-acetylamidopvrid-3-yl)-endo-3-cyano-8methyl-8-azabicyclo[3.2.1 Joctane.
Acetic anhydride (1.0ml) was added to exo-3-(5-aminopyrid-3-yl)-endo-3-cyano-8-methyI-8azabicyclo[3.2.1 Joctane (0.10g). After 3 days dilute sodium bicarbonate solution and ethyl
AP.00803
- 39 acetate were added followed by sodium bicarbonate and potassium carbonate to harify the mixture. The mixture was extracted with ethyl acetate and the extracts dried (MgSO4) and evaporated under reduced pressure to give exo-3-(5-acetylamidopyrid-3-yl)-endo-3-cyano-8methyl-8-azabicyclo[3.2.1 ]octane (0.107g).
EXAMPLE 42
This example illustrates the preparation of exo-3-(5-chloropyrid-3-yl)-endo-3-cyano-8-(acyanobenzyl)-8-azabicyclo[3.2.1]octane.
exo-3-(5-Chloropyrid-3-yl)-endo-3-cyano-8-azabicyclo[3.2.1]octane (2.0g) and benzaldehyde (0.89ml) were added to IM hydrochloric acid (20ml) and the mixture stirred for 20 minutes.
Sodium cyanide (0.549g) in water (6ml) was then added. After 18 hours ethanol (20ml) was added to give one phase. After 6 days the reaction mixture was partitioned between ethyl acetate and water and the organic layer was washed with water and brine, dried (MgSO4) and evaporated under reduced pressure. Chromatography [SiO2;
dichloromethane:methanol:triethylamine (99.4:0.5:0.1)] gave exo-3-(5-chloropyrid-3-yI)15 endo-3-cyano-8-(a-cyanobenzyl)-8-azabicyclo[3.2.1]octane (0.104g) m.p. 141-142°C.
EXAMPLE 43
This example illustrates the preparation of exo-3-f5-chloropyrid-3-yP-endo-3-cyano-8-(acarbamylbenzyl)-8-azabicyclo[3.2.1 ]octane.
Concentrated sulphuric acid (10ml) was added to exo-3-(5-chloropyrid-3-yl)-endo-3-cyano-820 (a-cyanobenzyl)-8-azabicyclo[3.2.1]octane (0.5lg) and the mixture stirred for 1 hour. Ice (lOOg) was added and the mixture basified with sodium bicarbonate solution. A precipitate formed which was collected by filtration, dissolved in ethyl acetate, dried (MgSO4) and evaporated under reduced pressure. Chromatography [SiO2; dichloromethane:methanol (99:1) to (98:2)] gave exo-3-(5-chloropyrid-3-yl)-endo-3-cyano-8-(a-carbamylbenzyn-825 azabicyclo[3.2.1]octane (0.181g) m.p. 193-195°C.
EXAMPLE 44
This example illustrates the preparation of exo-3-(5-iodopyrid-3-yI)-endo-3-cyano-8-methyl8-azabicyclo[3.2.1 ]octane.
Nickel(II) bromide (1.55ml of a 0.16M solution in Ν,Ν-dimethylformamide) was added to a stirred solution of tri(n-butyl)phosphine (0.124ml) in Ν,Ν-dimethylformamide (5ml) under nitrogen. Potassium iodide (3.96g) was then added followed by exo-3-(5-bromopyrid-3-yl)endo-3-cyano-8-methyl-8-azabicycloi3.2.11 octane (1.522g) and the mixture heated under
AP/P/ 97 / 0 1 1 39 *·.
- 40 reflux for 48 hours. The mixture was then cooled to room temperature and partitioned between water and ethyl acetate. The organic layer was dried (MgSO4), evaporated under reduced pressure and chromatographed [SiO2; dichloromethane:methanol (95:5)] to give exo3-(5-iodopyrid-3-yl)-endo-3-cyano-8-methyl-8-azabicyclo[3.2.1]octane (0.399g) m.p. 1445 145°C.
EXAMPLE 45
This example illustrates the preparation of exo-3-(5-trifluoromethylpyrid-3-yl)-endo-3-cyano8-methyl-8-azabicyclo[3.2.1 ]octane.
exo-3-f5-Iodopvrid-3-vl)-endo-3-cvano-8-methvI-8-azabicvcloi3.2. Hoc tane (0.50g) followed by copper(I) iodide were added to a stirred solution of sodium trifluoroacetate (2.6g) in Nmethylpyrrolidinone (5ml) and the mixture heated to 180°C. After 3 hours the mixture was cooled to room temperature, water added and extracted with dichloromethane. The organic layer was filtered and the filtrate dried (MgSO4) and evaporated under reduced pressure. Diethyl ether was added and the mixture extracted repeatedly with water. The aqueous fraction was evaporated under reduced pressure, basified with potassium carbonate and extracted with diethyl ether. The extracts were washed with IM hydrochloric acid and the aqueous fraction basified with potassium carbonate and extracted with diethyl ether. The extracts were dried (MgSO4) and evaporated under reduced pressure. Preparative thin layer chromatography [A12O3; diethyl ether] gave exo-3-(5-trifluoromethylpvrid-3-vl)-endo-320 cyano-8-methyl-8-azabicyclo[3.2.1]octane (0.027g) m.p. 118.2-118.5°C.
EXAMPLE 46
This example illustrates the preparation of exo-3-(5-chloropyrid-3-yI)-endo-3-cyano-8(mercaptothiocarbonyl)-8-azabicyclo[3.2.1]octane.
Carbon disulphide (0.12ml) was added to a stirred solution of exo-3-(5-chloropyrid-3-yI)25 endo-3-cyano-8-azabicyclo[3.2.1]octane (0.50g) in ethanol (5ml) at room temperature under nitrogen. After 4 hours the mixture was allowed to stand overnight. The precipitate was collected by filtration and washed with hexane to give exo-3-(5-chloropyrid-3-yl)-endo-3cyano-8-(mercaptothiocarbonyl)-8-azabicyclo[3.2.1]octane (O.5O9g) m.p. 224°C (decomposed).
EXAMPLE 47
This example illustrates the preparation of exo-3-(5-chloropvrid-3-yl)-endo-3-cyano-8(fluorocarbonyl)-8-azabicyclo[3.2.1 ]octane.
AP.ύ Ο β ο 3
- 41 Iodomethane (O.O8ml) was added to a stirred mixture of exo-3-(5-chioropyrid-3-yI)-endo-3cyano-8-(mercaptothiocarbonyl)-8-azabicyclo[3.2.1]octane (0.40g) in dimethyl sulphoxide (3ml) at room temperature. After 3 hours water was added and the mixture extracted with dichioromethane (x3). The combined extracts were washed with water (x2) and brine, dried (MgSO4) and evaporated under reduced pressure. Dichioromethane was added and the mixture washed with brine (x2), dried (MgSO4) and evaporated under reduced pressure to give exo-3-(5-chloropyrid-3-yl)-endo-3-cyano-8-(methylmercaptothiocarbonyl)-8azabicyclo[3.2.1]octane (0.187g).
Tetra(n-butyl)ammonium dihydrogentrifluoride (0.48g) was added to a solution of exo-3-(510 chloropyrid-3-yl)-endo-3-cyano-8-(methylmercaptothiocarbonyl)-8-azabicyclo[3.2.1]octane (0.180g) in dichioromethane at 0°C under nitrogen. N-Bromosuccinimide (0.38g) was then added. After 10 minutes the mixture was wanned to room temperature. After 2 hours the mixture was cooled to 0°C and allowed to stand over the weekend. The mixture was then stirred at room temperature for 8 hours and allowed to stand overnight. The mixture was diluted with dichioromethane and sodium bicarbonate and sodium bisulphite solutions added. The mixture was extracted with dichioromethane and the extracts dried (MgS04) and evaporated under reduced pressure. Ethyl acetate was added and the mixture washed with water (x2) and brine, dried (MgSO4) and evaporated under reduced pressure. Chromatography [SiO2; diethyl ethenhexane (80:20)] gave exo-3-(5-chloropyrid-3-yl)-endo| 20 3-cyano-8-(fluorocarbonyl)-8-azabicyclo[3.2.1]octane (0.10g) m.p. 165-167°C.
EXAMPLE 48 ' i
This example illustrates the preparation of exo-3-f5-chloropyrid-3-yl)-endo-3-cyano-8-(2.2difluoroethyl)-8-azabicyclo[3.2. l]octane.
2,2-Difluoroethyl bromide (1.08g), potassium carbonate (1.38g), potassium iodide (0.30g) and exo-3-(5-chloropyrid-3-yl)-endo-3-cyano-8-azabicyclo[3.2.1]octane (1.238g) were stirred at 50°C in ethanol (10ml). After 8 hours the mixture was allowed to stand at room temperature for 3 days. 2,2-Difluoroethyl bromide (1.08g), was then added and the mixture heated under reflux for 48 hours. 2,2-Difluoroethyl bromide (1.08g) and potassium carbonate (1.38g) were then added and the mixture heated under reflux for 24 hours. 2,2-Difluoroethyl bromide (1.08g) was then added and the mixture heated under reflux for 24 hours. The mixture was then cooled to room temperature and water added. The mixture was extracted with dichioromethane (x2) and the combined extracts washed with brine, dried (MgSO4) and
AP/P/ 9 7 / 0 1 1 3 9 evaporated under reduced pressure. Chromatography [SiO2; dichloromethane:methanol (96:4)] gave exo-3-(5-chloropvrid-3-vl)-endo-3-cyano-8-(2.2-difluoroethyI)-8azabicyclo[3.2.1]octane (0.278g) m.p. 101-104°C.
EXAMPLE 49
This example illustrates the preparation of exo-3-(5-chloropyrid-3-yl)-endo-3-cyano-8-(2phenylethyl)-8-azabicyclo[3.2.1 ]octane.
2-Phenylethyl bromide (0.222g), potassium carbonate (0.345g) and exo-3-(5-chloropyrid-3yl)-endo-3-cyano-8-azabicyclo[3.2.1 loctane (0.248g) were heated under reflux in ethanol (2ml) for 9 hours. 2-Phenylethyl bromide (O.lg) was added and the mixture refluxed for 5 hours. The mixture was then cooled to room temperature and water added. The mixture was extracted with diehloromethane (x2) and the combined extracts washed with brine, dried (MgSO4) and evaporated under reduced pressure. Chromatography [SiO2; dichloromethane:methanol (98:2)] gave exo-3-(5-chloropyrid-3-vl)-endo-3-cyano-8-(2phenylethyl)-8-azabicyclo[3.2.1]octane (0.08g).
EXAMPLE 50
This example illustrates the preparation of exo-3-(5-hydroxypyrid-3-vl)-endo-3-cyano-8methyl-8-azabicyclo[3.2.1 ]octane.
Pyridinium hydrochloride (l.Og) and exo-3-(5-methoxypyrid-3-yl)-endo-3-cyano-8-methyl-8azabicyclo[3.2.1 ]octane (0.20g) were heated together at 150°C for 5 hours. The mixture was then cooled to room temperature, water added and the mixture basified with sodium bicarbonate solution and extracted with ethyl acetate (x3). The aqueous fraction was neutralised with dilute hydrochloric acid and extracted with ethyl acetate (x3). The combined organic extracts were washed with water, dried (MgSO4) and evaporated under reduced pressure. Chromatography [SiO2; dichloromethane:methanol (90:10) to (80:20)] gave a gum which crystallised on addition of diethyl ether to give exo-3-(5-hydroxypyrid-3-yi)-endo-3cyano-8-methyl-8-azabicyclo[3.2.1 loctane (0.049g) m.p. 171-172°C.
EXAMPLE 51
This example illustrates the preparation of exo-3-(5-chioropyrid-3-yl)-endo-3-cyano-8benzyl-8-azabicyclo[3.2.1 ]octane.
exo-3-Cyano-8-methyl-8-azabicyclo[3.2.1 ]octane (0.5g) in tetrahydrofuran (3ml) was added to a solution of lithium diisopropylamide [made by adding n-BuLi (1.6ml of a 2.5M solution in hexane) to diisopropylamine (0.4g) in tetrahydrofuran (3ml)] at -25°C under nitrogen.
AP.00803
- 43 After 15 minutes at the mixture was cooled to -78°C and 3,5-dichloropyridine (0.588g) in tetrahydrofuran (3ml) was added. After 1 hour the mixture was allowed to warm to room temperature and stand overnight. Water was then added and the resulting mixture extracted with ethyl acetate (x3). The combined extracts were washed with brine and water, dried (MgSO4) and evaporated under reduced pressure. Chromatography [SiCL; dichloromethane:methanol (90:10)] gave exo-3-(5-chloropyrid-3-yI)-endo-3-cyano-8-methyl-8azabicyclo[3.2.1]octane (0.249g).
Vinyl chloroformate (2.6ml) in tetrahydrofuran (5ml) was added to a stirred solution of exo3-(5-chloropyrid-3-yl)-endo-3-cyano-8-methyl-8-azabicvcloi3.2.1]octane (2.6g) in tetrahydrofuran (25ml) at 0°C. The mixture was allowed to warm to room temperature over -, 1 hour, refluxed for 2 hours and then allowed to cool to room temperature. After 20 hours the mixture was partitioned between water and ethyl acetate and the organic layer was separated, washed with water and dried (MgSO4). Evaporation under reduced pressure gave exo-3-(5-chloropyrid-3-yl)-endo-3-cyano-8-( vinyloxycarbonyl)-8-azabicyclo[3.2.1 ]octane (2.0g).
exo-3-f5-ChIoropvrid-3-vI)-endo-3-cvano-8-(vinv loxycarbonyl)-8-azabicyclo[3.2.1 ] octane (2.6g) was dissolved in methanol (50ml) and concentrated hydrochloric acid (7ml) added. The mixture was refluxed for 3 hours after which the mixture was evaporated under reduced pressure and basified with aqueous sodium carbonate. The resulting mixture was extracted
J 20 with ethyl acetate and evaporated under reduced pressure to give a brown solid. This was :¾ then washed with hexane to give exo-3-(5-chloropyrid-3-yl)-endo-3-cyano-8azabicyclo[3.2.1]octane (1.2g).
exo-3-(5-Chloropyrid-3-yl)-endo-3-cyano-8-azabicyclo[3.2.1]octane (0.104g) in ethanol (5ml) was added to benzyl bromide (0.079g) and potassium carbonate (0.12g) and the mixture refluxed for 18 hours. After cooling to room temperature the mixture was evaporated under reduced pressure and partitioned between water and ethyl acetate. The organic layer was separated and evaporated under reduced pressure. Preparative thin layer chromatography [SiO2; dichloromethane:methanol (97:3)] gave exo-3-(5-chloropyrid-3-yI)endo-3-cyano-8-benzyl-8-azabicyclo[3.2.l]octane (0.077g).
EXAMPLE 52
This example illustrates the preparation of exo-3-(5-chloropvrid-3-yl)-endo-3-cyano-8(pentafluorophenylmethyl)-8-azabicyclo[3.2.1]octane.
AP/P/ 9 7/0113» exo-3-(5-Chloropyrid-3-vl)-endo-3-cyano-8-azabicvcloi3.2. ljoctane (0.248g), 2,3,4,5,6pentafluorobenzyl bromide (0.313g), potassium carbonate (0.345g) and ethanol (2ml) were stirred under reflux for 3 hours. The mixture was then evaporated under reduced pressure and water added. The mixture was then extracted with dichloromethane (x3) and the combined extracts were washed with brine, dried (MgSO4) and evaporated under reduced pressure to give an oil which crystallised on standing. The crystals were washed with a small volume of ether to - give exo-3-(5-chloropyrid-3-vl)-endo-3-cyano-8(pentafluorophenylmethyl)-8-azabicyclo[3.2.ljoctane (0.258g) m.p. 143-144°C.
EXAMPLE 53
This example illustrates the preparation of potassium exo-3-(5-chloropvrid-3-yl)-endo-3cyano-8-(4-carboxylatobenzyl)-8-azabicyclo[3.2. ljoctane.
exo-3-(5-Chloropyrid-3-yl)-endo-3-cvano-8-azabicyclor3.2.1 joctane (0.248g) 4bromomethylbenzoic acid (0.258g), potassium carbonate (0.345g) and ethanol (2ml) were stirred under reflux for 2.5 hours. The mixture was then diluted with ethanol, filtered and the filtrate evaporated under reduced pressure to give potassium exo-3-f5-chloropyrid-3-yl)endo-3-cyano-8-(4-carboxylatobenzyl)-8-azabicyclo[3.2.1 joctane (0.292g).
EXAMPLE 54
This example illustrates the preparation of exo-3-(5-chloropvrid-3-vI)-endo-3-cyano-8-(3chloro-4-fluorobenzyl)-8-azabicyclo[3.2. ljoctane.
exo-3-(5-Chloropyrid-3-yl)-endo-3-cyano-8-azabicyclo[3.2.ljoctane (0.495g), 3-chioro-4fluorobenzaldehyde (0.317g) and formic acid (96%, 0.230g) were heated under reflux for 5 hours. The mixture was then cooled to room temperature, basified with dilute sodium hydroxide and extracted with dichloromethane (x2). The combined extracts were washed with brine, dried (MgSO4), and evaporated under reduced pressure. Chromatography [SiO2; dichloromethane:methanol (100:0) to (95:5)j gave exo-3-(5-chloropyrid-3-yl)-endo-3-cyano-8(3-chloro-4-fluorobenzyl)-8-azabicyclo[3.2.ljoctane (0.290g) m.p. 95-97°C.
EXAMPLE 55
This example illustrates the preparation of exo-3-(5-chloropyrid-3-yl)-endo-3-cvano-8-(pyrid2-ylmethyl)-8-azabicyclo[3.2. ljoctane.
2-Picolyl chloride hydrochloride (0.36lg), potassium carbonate (0.828g) and exo-3-(5chloropyrid-3-yl)-endo-3-cyano-8-azabicyclo[3.2.ljoctane (0.495g) were heated under reflux in ethanol (4ml) for 2 hours. The mixture was then cooled to room temperature and water
AP.00803
- 45 added. The mixture was extracted with dichloromethane (x2) and the combined extracts washed with brine, dried (MgSO4) and evaporated under reduced pressure. Chromatography [SiCh; dichloromethanezmethanol (100:0) to (95:5)] gave exo-3-(5-chloropyrid-3-yl)-endo-3cyano-8-(pyrid-2-ylmethyl)-8-azabicyclo[3.2.1]octane (0.447g) m.p. 123-125°C.
EXAMPLE 56
This example illustrates the preparation of exo-3-(5-chloropyrid-3-yl)-endo-3-cyanc>-8-(f2methylthiazol-4-yl)methyl)-8-azabicyclo[3.2.1 ]octane.
4-Chloromethyl-2-methylthiazole hydrochloride (0.202g), potassium carbonate (0.483g) and exo-3-(5-chloropvrid-3-vl)-endo-3-cvano-8-azabicvcloi3.2.11octane (0.247g) were heated under reflux in ethanol (2ml) for 1.5 hours. 4-Chloromethyl-2-methylthiazole hydrochloride (0.40g) was then added and the mixture refluxed for 30 minutes. The mixture was then cooled to room temperature and water added. The mixture was extracted with dichloromethane (x2) and the combined extracts washed with brine, dried (MgSO4) and evaporated under reduced pressure. Chromatography [SiC>2; dichloromethanezmethanol (99:1) to (95:5)] gave exo-3-f5-chloropyrid-3-yl)-endo-3-cvano-8-((2-methylthiazol-4yl)methyl)-8-azabicyclo[3.2.1]octane (0.269g) m.p. 81-83°C.
EXAMPLE 57 •Lb»/
This example illustrates the preparation of exo-3-(5-chloropyrid-3-yI)-endo-3-cyano-8-((3.5dimethylisoxazol-4-yl)methyl)-8-azabicyclo[3.2.1 ]octane. z 20 4-Chloromethyl-3,5-dimethylisoxazole (0.160g), potassium carbonate (0.345g), potassium iodide (0.02g) and exo-3-(5-chloropyrid-3-yl)-endo-3-cvano-8-azabicycloi3.2.1'loctane (0.247g) were heated under reflux in ethanol (2ml) for 3 hours. The mixture was then cooled to room temperature and water added. The mixture was extracted with dichloromethane (x2) and the combined extracts washed with brine, dried (MgSO4) and evaporated under reduced 25 pressure. Filtration [SiO2; dichloromethanezmethanol (98:2)] gave exo-3-f5-chloropyrid-3-yI)endo-3-cyano-8-((3,5-dimethylisoxazoM-yl)methyl)-8-azabicyclo[3.2.1]octane (0.258g) m.p. 95-99°C.
AP/P/ 9 7/01139
EXAMPLE 58
This example illustrates the preparation of exo-3-(5-chloropvrid-3-yl)-endo-3-cyano-8-(530 chlorothiophen-2-yl)-8-azabicy clo[3.2.1 ]octane.
2-Chloro-5-chloromethylthiophene (0.367g), potassium carbonate (0.690g) and exo-3-(5chloropyrid-3-yl)-endo-3-cyano-8-azabicyclo[3.2.1]octane (0.495g) were heated under reflux in ethanol (2ml) for 1.5 hours. Potassium iodide (0.02g) was then added and the mixture refluxed for 1.5 hours. The mixture was then cooled to room temperature and water added. The mixture was extracted with dichloromethane (x2) and the combined extracts washed with brine, dried (MgSO4) and evaporated under reduced pressure. Chromatography [SiO2; dichloromethane:methanol (100:0) to (96:4)] gave exo-3-(5-chIoropvrid-3-vl)-endo-3-cyano8-(5-chlorothiophen-2-yl)-8-azabicyclo[3.2.1]octane (0.37g) m.p. 119-121°C.
EXAMPLE 59
This example illustrates the preparation of exo-3-(5-chloropyrid-3-yI)-endo-3-cyano-8-((5chloro- l,2,3-thiadiazol-4-yl)methyl)-8-azabicycio[3.2.1] octane.
5-Chloro-4-chloromethyl-l,2,3-thiadiazole (0.187g), potassium carbonate (0.345g) and exo3-(5-chloropyrid-3-yl)-endo-3-cyano-8-azabicyclo[3.2.1]octane (0.248g) were heated under reflux in ethanol (2ml) for 4 hours. The mixture was then cooled to room temperature and water added. The mixture was extracted with dichloromethane (x2) and the combined extracts washed with brine, dried (MgSO4) and evaporated under reduced pressure. Chromatography [SiO2; dichloromethane:methanol (100:0) to (98:2)] gave exo-3-f5chloropyrid-3-yl)-endo-3-cyano-8-((5-chloro-1,2,3-thiadiazol-4-yl)methyl)-8azabicyclo[3.2.1]octane (0.148g).
EXAMPLE 60
This example illustrates the preparation of exo-3-f5-fIuoropyrid-3-yl)-endo-3-cyano-8methyl-8-azabicyclo[3.2.1]octane.
exo-3-(5-Aminopyrid-3-yl)-endo-3-cyano-8-methyl-8-azabicyclo[3,2.1 ]octane (0.40g) in dichloromethane (150ml) was added to boron trifluoride etherate (1.5ml) at -10 to -15°C. After a few minutes t-butyl nitrite (2ml) was added and the mixture allowed to warm to room temperature and stand overnight. The solid precipitate was collected and heated to cause decomposition. The residue was dissolved in 2M hydrochloric acid, washed with ethyl acetate, basified and extracted with ethyl acetate. The extracts were dried (MgSO4), evaporated under reduced pressure and chromatographed [SiO2; dichloromethane:methanol (90:10)] to give exo-3-(5-fluoropyrid-3-yl)-endo-3-cyano-8-methyl-8-azabicyclo[3.2.1]octane (0.089g).
EXAMPLE 61
This example illustrates the preparation of exo-3-(5-(pyrrol-l-yl)pyrid-3-yl)-endo-3-cyano-8methyl-8-azabicyclo[3.2.1 ]octane.
ΑΡ.00803
-472,5-Dimethoxytetrahydrofuran (0.53ml) was added to a mixture of exo-3-(5-aminopyrid-3yl)-endo-3-cyano-8-methyl-8-azabicyclo[3.2.1]octane and acetic acid (13ml). After 5 minutes the mixture was heated at reflux for 1 hour and then allowed to cool to room temperature and stand overnight. Ethyl acetate was added and the mixture extracted with 2M hydrochloric acid and water. The combined extracts were basified with potassium carbonate and extracted with ethyl acetate. The extracts were dried (MgSO4) and evaporated under reduced pressure to give exo-3-(5-(pyrrol-l-yl)pyrid-3-yl)-endo-3-cyano-8-methyl-8-azabicyclo[3.2.1]octane (0.105g).
EXAMPLE 62
This example illustrates the preparation of exo-3-(5-(l-ethoxyvinyl)pyrid-3-yl)-endo-3-cyano8-methyl-8-azabicyclo[3.2. l)octane.
(1-Ethoxy vinyl)tri-n-butyltin ((0.82ml) was added to a stirred mixture of exo-3-(5-iodopyrid3-yl)-endo-3-cyano-8-methyl-8-azabicyclo[3.2.1]octane (0.817g) and £i,N15 dimethylformamide (30ml) at room temperature under nitrogen. Bis(triphenylphosphine)palladium(II) chloride (0.65g) was then added and the mixture heated at 130°C for 3 hours. The mixture was then allowed to cool to room temperature, water added and the mixture extracted with dichioromethane (x3). The combined extracts were washed with brine, dried (MgSO4) and evaporated under reduced pressure. Chromatography [SiO2; dichloromethanermethanol (91:9)] followed by chromatography [SiO2; ? dichloromethanermethanol (98:2) to (92:8] gave exo-3-(5-(l-ethoxy vinyl)pyrid-3-yl)-endo-3cyano-8-methyl-8-azabicyclo[3.2.1 ] octane (0.22g).
EXAMPLE 63
AP/P/ 9 7/01 139
This example illustrates the preparation of exo-3-f5-acetylpyrid-3-vl)-endo-3-cyano-8-methyl25 8-azabicyclo[3.2.1]octane.
2M Hydrochloric’acid (1ml) was added to a stirred mixture of exo-3-(5-( 1 -ethoxyvinvDpyrid3-yl)-endo-3-cyano-8-methyl-8-azabicyclo[3.2.1]octane (0.18g) in acetone (2ml). After 3 hours the mixture was allowed to stand overnight. The mixture was poured onto saturated sodium bicarbonate solution and the resulting mixture extracted with dichioromethane (x3).
The combined extracts were dried (MgSO4), evaporated under reduced pressure and chromatographed [SiO2; dichloromethane:methanol (93:7)] to give exo-3-(5-acetylpyrid-3yl)-endp-3-cyano-8-methyl-8-azabicyclo[3.2.1]octane (0.13g).
- 48 EXAMPLE 64
This example illustrates the preparation of exo-3-(5-ethynylpyrid-3-yI)-endo-3-cyano-8methyl-8-azabicyclo[3.2.1 joctane.
exo-3-(5-Iodopyrid-3-vl)-endo-3-cvano-8-methvl-8-azabicycloi3.2-Hoc tane (0.50g) in tetrahydrofuran (1ml) was added dropwise to a stirred mixture of trimethylsilylacetylene (0.22ml), diethylamine (1.13ml), copper(I) iodide (0.0 lg) and tetrakis(triphenylphosphine)palladium(0) (0.02g) at room temperature under nitrogen. After 3 hours the mixture was allowed to stand at room temperature for 24 hours and then evaporated under reduced pressure. Dichioromethane (10ml) was added followed by tetrabutylammonium fluoride (1.7ml of a IM solution in tetrahydrofuran) and the mixture stirred at room temperature for 1.5 hours. Water was added and the mixture extracted with dichioromethane (x2). The combined extracts were washed with brine, dried (MgSO4), evaporated under reduced pressure and chromatographed [SiCh; dichloromethane:methanol (95:5) to (90:10)] to give a crude product. Chromatography [SiCh; dichloromethane:methanol (92:8)] followed by dissolving the product in dichlorome±ane, washing with water (x2) and brine, drying (MgSO4) and evaporating under reduced pressure gave exo-3-(5-ethynylpyrid-3-yl)-endo-3-cyano-8-methyl-8-azabicyclo[3.2.1 joctane (0.40g).
EXAMPLE 65
This example illustrates the preparation of exo-3-(5-chloropyrid-3-yl~)-endo-3-cyano-8(1-hydroxy-1-cyano-2-phenylprop-2-yl)-8-azabicyclo[3.2.1 ]octane.
Sodium cyanoborohydride (0.033g) was added to a stirred solution of isopropylamine (0.045ml) and exo-3-(5-chloropyrid-3-yl)-endo-3-cyano-8-(2-phenyl-3-oxo-prop-2-yl)-8azabicyclo[3.2.1 joctane (0.20g) in methanol (2ml). Methanolic hydrogen chloride was then added to give pH5. After 2 hours the mixture was allowed to stand at room temperature for 2 days and isopropylamine (0.045ml) and sodium cyanoborohydride (0.033g) were added. After stirring at room temperature for 6 hours saturated sodium bicarbonate was added and the mixture extracted with dichioromethane (x3). The combined extracts were washed with brine, dried (MgSO4), evaporated under reduced pressure and chromatographed [SiCh; dichloromethane:methanol (100:0) to (90:10)] to give exo-3-(5-chloropyrid-3-yl)-endo-3cyano-8-(l-hydroxy-l-cyano-2-phenyiprop-2-yl)-8-azabicyclo[3.2.1]octane (0.75g) m.p. 172175°C.
AP.00803
- 49 EXAMPLE 66
This example illustrates the preparation of exo-3-(5-chloropvrid-3-vI)-endo-3-cyano-8-(2(isopropylamino)-2-phenylprop-l-yl)-8-azabicyclo[3.2. ljoctane.
Triethylamine (0.1ml) and methanesulphonyl chloride (0.053ml) were added to a stirred solution of exo-3-(5-chloropyrid-3-yl)-endo-3-cyano-8-f2-phenyl-3-hydroxyprop-2-yI)-8azabicyclo[3.2. ljoctane (0.25g) in dichloromethane (5ml) at room temperature. After 2 hours isopropylamine (0.65ml) was added. After 2 hours the mixture was allowed to stand at room temperature overnight and dichloromethane then added. The mixture was washed with water (x2) and brine, dried (MgSO4), evaporated under reduced pressure and chromatographed [SiO2; dichloromethane:methanol (98:2) to (95:5)]to give exo-3-(5=-4 chloropyrid-3-yl)-endo-3-cyano-8-(2-(isopropylamino)-2-phenylprop-1 -y 1)-8azabicyclo[3.2.ljoctane (0.24g).
EXAMPLE 67
This example illustrates the preparation of exo-3-(5-chloropyrid-3-yl)-endo-3-cyano-815 cyanomethyl-8-azabicyclo[3.2. ljoctane.
t
Bromoacetonitrile (0.85ml) was added to a mixture of exo-3-(5-chloropvrid-3-yl)-endo-3cyano-8-azabicyclo[3.2.ljoctane (2.0g) and potassium carbonate (2.23g) in ethanol (10ml) and the mixture heated at reflux for 3 hours. The mixture was then cooled to room temperature, filtered (celite) and washed through with dichloromethane. The filtrates were . J 20 evaporated under reduced pressure, chromatographed [SiO2; dichloromethane-.methanol Lfy (99:1)] and recrystallised (ethyl acetate/hexane) to give exo-3-(5-chloropyrid-3-yl)-endo-3cyano-8-cyanomethyl-8-azabicyclo[3.2. ljoctane (1.36g). m.p. 149-151 °C.
EXAMPLE 68
This example illustrates the preparation of exo-3-(5-chloropyrid-3-yl)-endo-3-cyano-8-(l25 (ethoxycarbonyl)ethyl)-8-azabicyclo[3.2. ljoctane.
Ethyl 2-bromopropionate (0.29ml) was added to a mixture of exo-3-(5-chloropyrid-3-yl)endo-3-cyano-8-azabicyclo[3.2.1 loctane (0.5g) and potassium carbonate (0.42g) in tetrahydrofuran (8ml) and the mixture heated at reflux for 24 hours. The mixture was then cooled to room temperature, filtered (celite) and washed through with dichloromethane. The filtrates were evaporated under reduced pressure and chromatographed [SiO2;
dichloromethane:methanol (100:0 to (98:2)] to give exo-3-(5-chloropyrid-3-yl)-endo-3cyano-8-( 1 -(ethoxycarbonyl)ethyl)-8-azabicyclo[3.2.1 joctane (0.49g).
AP/P/ 97/01139
EXAMPLE 69
This example illustrates the preparation of exo-3-(5-chloropyrid-3-yl)-endo-3-cyano-8-(6fluoropyrid-2-yl)-8-azabicyclo[3.2.1]octane.
2,6-Difluoropyridine (0.37ml), potassium carbonate (1.12g) and exo-3-(5-chloropyrid-3-yl)endo-3-cvano-8-azabicyclo[3.2. lloctane (LOg) were heated at 140°C in Nmethylpyrrolidinone (10ml) for a total of 8 hours. The mixture was then cooled to room temperature, poured into water and the resulting mixture extracted with ethyl acetate (x3). The combined extracts were washed with brine, dried (MgSO4), evaporated under reduced pressure and chromatographed [SiO2; hexane-.ethyl acetate (90:10)) to give exo-3-(5chloropyrid-3-yl)-endo-3-cyano-8-(6-fluoropyrid-2-yl)-8-azabicyclo[3.2.1)octane (0.796g) m.p. 131.5-132.5°C.
EXAMPLE 70
This example illustrates the preparation of exo-3-(5-chloropyrid-3-yl)-endo-3-cyano-8-(5chlorothiazol-2-yl)-8-azabicyclo[3.2.1]octane.
2-Bromo-5-chlorothiazole (2.4g), potassium carbonate (1.67g) and exo-3-f5-chloropyrid-3yl)-endo-3-cyano-8-azabicyclo[3.2.1 loctane (l.Og) were heated at 140°C in Nmethylpyrrolidinone (10ml) for a total of 10 hours. The mixture was then cooled to room temperature, poured into water and the resulting mixture extracted with ethyl acetate (x3). The combined extracts were washed with brine, dried (MgSO4), evaporated under reduced pressure and chromatographed [SiO2; hexane:ethyl acetate (90:10)]. Recrystallisation (hexane) gave exo-3-f5-chloropyrid-3-yl)-endo-3-cyano-8-(5-chlorothiazol-2-yB-8azabicyclo[3.2.1]octane (0.17g) m.p. 111-112°C.
EXAMPLE 71
This example illustrates the preparation of exo-3-(5-chloropyrid-3-yB-endo-3-cyano-8pentafluorophenyl-8-azabicyclo[3.2.1]octane.
Hexafluorobenzene (0.93ml), potassium carbonate (1.12g) and exo-3-(5-chloropyrid-3-vl)endo-3-cyano-8-azabicyclo[3.2.1]octane (LOg) were heated at 150°C in Nmethylpyrrolidinone (10ml) for 5 hours. Hexafluorobenzene (0.93ml) and potassium carbonate (1.12g) were added and the mixture heated at 160°C for 7 hours. The mixture was then cooled to room temperature, poured into water and the resulting mixture extracted with ethyl acetate (x3). The combined extracts were washed with brine, dried (MgSO4),
AP.00803
- 51 evaporated under reduced pressure and chromatographed [SiO2; hexaneiethyl acetate (90:10)] to give exo-3-(5-chloropyrid-3-yl')-endo-3-cyano-8-pentafluomphRny1-Razabicyclo[3.2.1]octane (0.55g).
EXAMPLE 72
This example illustrates the preparation of exo-3-(5-chloropyrid-3-yI)-endo-3-cyano-8-cyano8-azabicyclo[3.2. l]octane.
Tosyl cyanide (0.88ml) was added dropwise to a stirred mixture of exo-3-(5-chloropyrid-3yl)-endo-3-cyano-8-azabicyclo[3.2.1]octane (l.Og) and Ν,Ν-diisopropylethylamine (0.85ml) in tetrahydrofuran (5ml) at room temperature. After 6 hours the mixture was allowed to stand at room temperature overnight, poured into water and extracted with ethyl acetate (x3).
7 The combined extracts were washed with water and brine, dried (MgSO4), evaporated under reduced pressure and chromatographed [SiO2; hexane:ethyl acetate (90:10)]. Recrystallisation (hexane/ethyl acetate) gave exo-3-(5-chloropyrid-3-yl)-endo-3-cyano-8cyano-8-azabicyclo[3.2.1]octane (0.20g) m.p. 168-170°C.
EXAMPLE 73 t
This example illustrates the preparation of exo-3-(5-chloropvrid-3-vI)-endo-3-cyano-8methoxy-8-azabicyclo[3.2.1 ]octane.
Ν,Ν-Diisopropylethylamine (14.5ml) was added dropwise to a stirred suspension of Omethylhydroxylamine hydrochloride (2.32g) in isopropyl alcohol (25ml). After 30 minutes cyclohepta-2,6-dienone (3.0g) in isopropyl alcohol (5ml) was added dropwise. After 24 ) hours Ν,Ν-diisopropylethylamine (4.9ml) was added. After 6 hours the mixture was allowed to stand at room temperature overnight. The mixture was evaporated under reduced pressure, diethyl ether added and the resulting mixture extracted with 2M hydrochloric acid (x3). The combined aqueous fractions were washed with diethyl ether (x3), neutralised with sodium hydroxide and extracted with diethyl ether (x3). The combined extracts were washed with brine, dried (MgSO4) and evaporated under reduced pressure. Kugelrohr distillation gave 8-methoxy-8-azabicyclo[3.2.1]octan-3-one (0.86g).
Tosylmethyl isocyanide (2.52g) was added to a stirred suspension of potassium t-butoxide (2.17g) in 1,2-dimethoxyethane (10ml) at such a rate to keep the temperature below 10°C.
After 45 minutes 8-methoxy-8-azabicyclo[3.2.1]octan-3-one (l.Og) in 1,2-dimethoxyethane
I (10ml) was added dropwise. After 30 minutes the mixture was allowed to warm to room temperature. After 4 hours the mixture was allowed to stand at room temperature overnight
AP/P/ 9 7/01 139 and water was then added. The resulting mixture was extracted with ethyl acetate (x3) and the combined extracts washed with brine, dried (MgSO4) and evaporated under reduced pressure. Chromatography [SiO2; hexane:ethyl acetate (90:10)] gave exo-3-cyano-8methoxy-8-azabicyclo[3.2.1]octane (0.40g).
Lithium bis(trimethylsilyl)amide (2.42ml of a 1M solution in tetrahydrofuran) was added dropwise to a stirred solution of exo-3-cyano-8-methoxy-8-azabicyclo[3.2.1]octane (0.40g) and 3,5-dichloropyridine (0.358g) in tetrahydrofuran (5ml) at 0°C. After 1 hour the mixture was allowed to warm to room temperature. After 5 hours water was added and the mixture extracted with ethyl acetate (x3). The combined extracts were washed with brine, dried (MgSO4) and evaporated under reduced pressure. Preparative thin layer chromatography [SiO2; ethyl acetate] gave exo-3-(5-chloropyrid-3-yl)-endo-3-cvano-8-methoxy-8azabicyclo[3.2.1]octane (0.192g) m.p. 107.5-108.5°C.
EXAMPLE 74
This example illustrates the preparation of exo-3-(5-chloropyrid-3-yl)-endo-3-cyano-8-(2(ethoxycarbonyl)ethyl)-8-azabicyclo[3.2.1]octane.
Sodium hydride (0.095g of an 80% dispersion in oil) was added to exo-3-(5-chloropyrid-3vl)-endo- 3-cyano-8-azabicycIoi 3.2.1 loctane (0.75g) and ethyl acrylate (2.0g) in tetrahydrofuran. The mixture was refluxed for 8 hours then allowed to cool to room temperature, water added and the mixture extracted with ethyl acetate (x2). The combined extracts were washed with brine, dried (MgSO4) and evaporated under reduced pressure. Chromatography [SiO2; chloroform:methanol (95:5)] followed by chromatography [SiO2; ethyl acetate:dichloromethane (80:20)] gave exo-3-(5-chloropyrid-3-yl)-endo-3-cyano-8-(2(ethoxycarbonyl)ethyl)-8-azabicyclo[3.2.1 ]octane.
EXAMPLE 75
This example illustrates the preparation of exo-3-(5-chloropyrid-3-vI )-endo-3 -cy ano-8-f2carboxyethyl)-8-azabicyclo[3.2.1]octane.
3M Sodium hydroxide (4ml) was added to a stirred solution of exo-3-(5-chloropyrid-3-yl)endo-3-cyano-8-(2-(ethoxycarbonyl)ethyl)-8-azabicyclo[3.2.1]octane (0.41g) in ethanol (8ml) at room temperature. After 24 hours the mixture was basified to pH9 and evaporated under reduced pressure. The product was azeotroped with methanol/toluene and chromatographed i
[SiO2; dichloromethane:methanol (75:25)] to give exo-3-(5-chloropyrid-3-yl)-endo-3-cyano8-(2-carboxyethyl)-8-azabicyclo[3.2.1]octane (0.21g) m.p. 180-181°C.
ΑΡ.00803
- 53 EXAMPLE 76
This example illustrates the preparation of exo-3-(5-chloropyrid-3-yl)-endo-3-cyano-8-fO.Odiethylphosphonomethyl)-8-azabicyclo[3.2.1 ]octane.
exo-3-(5-Chloropyrid-3-yl)-endo-3-cyano-8-azabicyclo[3.2.1]octane (0.20g), 0,05 diethylphosphonomethyl inflate (0.245g) and potassium carbonate (0.15g) were heated under reflux in tetrahydrofuran (8ml). After 3 hours the mixture was cooled to room temperature, filtered and evaporated ' under reduced pressure. Chromatography [SiO2; dichloromethane:methanol (96:4)] followed by high pressure liquid chromatography [SiO2; dichloromethane:methanol (96:4)] gave exo-3-(5-chloropyrid-3-yD-endo-3-cyano-8-(Q.O10 diethylphosphonomethyl)-8-azabicyclo[3.2.1]octane m.p. 69-70°C.
! EXAMPLE 77
This example illustrates the preparation of exo-3-(5-chloropyrid-3-yl)-endo-3-cyano-8phosphonomethyl-8-azabicyclo[3.2. l]octane.
Trimethylsilyl bromide (1.5ml) was added dropwise to a stirred solution of exo-3-(515 chloropyrid-3-yI)-endo-3-cyano-8-(0.0-diethylphosphonomethyI)-8-azabicyclo[3.2.11octane (0.56g) in dichloromethane (30ml) at 0°C. After 30 minutes the mixture was allowed to warm to room temperature. After 7 hours trimethylsilyl bromide (0.8ml) was added, after 23 hours more trimethylsilyl bromide (0.5ml) was added and after 18 hours further trimethylsilyl bromide (0.5ml) was added. After 24 hours the mixture was evaporated under reduced pressure, water added and the mixture filtered. After 10 minutes the filtrate was azeotroped j with methanol/to'luene to give exo-3-(5-chloropyrid-3-yI)-endo-3-cyano-8-phosphonomethvl8-azabicyclo[3.2.1]octane (0.49g) m.p. 242-245°C.
EXAMPLE 78
This example illustrates the preparation of exq-3-(5-chloropyrid-3-yl)-endq-3-cyano-8-(225 cyanoethyl)-8-azabicyclo[3.2.1 ]octane.
3-Bromopropionitrile (0.174ml) was added to exo-3-f5-chloropyrid-3-yl)-endo-3-cvano-8azabicyclo[3.2.1]octane (0.40g) and potassium carbonate (0.45g) in ethanol (10ml) and the mixture heated under reflux for 16 hours. 3-Bromopropionitrile (0.13ml) was added and the mixture refluxed for 3 hours and allowed to cool to room temperature. Water was added and the mixture extracted with dichloromethane (x3). The combined extracts were washed with brine, dried (MgSO4) and evaporated under reduced pressure. Chromatography [SiO2;
AP/P/ 9 7/01 139 dichloromethane:methanol (100:0) to (98:2] gave exo-3-(5-chloropyrid-3-vl)-endo-3-cyano8-(2-cyanoethyl)-8-azabicyclo[3.2.1 joctane (0.343g).
EXAMPLE 79
Thi<; example illustrates the preparation of exo-3-(5-chloropyrid-3-vl)-endo-3-cyano-8-f 1.15 dimethyl-2,2,2-trifiuoroethyl)-8-azabicyclo[3.2.1 joctane.
4AMolecular sieves (l.Og) were added to a suspension of exo-3-(5-chloropyrid-3-yl)-endo-3cyano-8-azabicyclo[3.2.1 joctane hydroperchlorate (3.42g) in acetone (30ml) and the mixture heated under reflux for 5 hours. The mixture was then allowed to cool to room temperature and filtered to give exo-3-(5-chloropyrid-3-yl)-endo-3-cyano-8-isopropylene-810 azabicyclo[3.2.1 joctanium perchlorate (0.279g).
Trimethyl(trifluoromethyl)silane (5.2ml of a 0.5M solution in tetrahydrofuran) was added to a suspension of exo-3-(5-chloropyrid-3-yl)-endo-3-cyano-8-isopropylene-8azabicyclo[3.2.1 joctanium perchlorate (0.50g) in tetrahydrofuran (5ml). Cesium fluoride (0.39g) was added and the mixture placed in an ultrasound bath for 2.5 hours. The mixture was then added to water and the resulting mixture extracted with dichloromethane (x3). The combined extracts were washed with brine, dried (MgSO4) and evaporated under reduced pressure. Chromatography [SiO2; dichloromethane:methanol (97:3)] followed by preparative thin layer chromatography [SiO2; dichloromethane:methanol (98:2)] gave exo-3-(5chloropyrid-3-yl)-endo-3-cyano-8-( 1,1 -dimethyl-2,2,2-trifluoroethy 1)-820 azabicyclo[3.2.1joctane (0.02g).
EXAMPLE 80
This example illustrates the preparation of exo-3-(5-(2.2.2-trifIuoroethoxv)pyrid-3-vl)-endo3-cyano-8-methyl-8-azabicyclo[3.2.1 joctane.
Sodium (0.46g) was added portionwise to a solution of 2,22,-trifluoroethanol (2.3ml) in N25 methylpyrrolidinone (20ml) under nitrogen. Tetraphenylphosphonium bromide (0.05g) and exo-3-(5-chloropyrid-3-yl)-endp-3-cyano-8-methyl-8-azabicyclo[3.2.1 joctane (2.6g) were added and the mixture heated at 110°C for 18 hours and 140°C for 5 hours. Sodium (0.6g) was added to a solution of 2,22,-trifluoroethanol (3ml) in N-methylpyrrolidinone (5ml) and after 30 minutes the resulting mixture was added to the reaction mixture. After 6 hours at
140°C the mixture was cooled to room temperature and added to water. The mixture was extracted with diethyl ether (x2) and the combined extracts were washed with water, dried (MgSO4) and evaporated under reduced pressure. The resulting mixture was filtered [SiO2;
AP.00803
- 55 dichloromethane:methanol (95:5)] and chromatographed [SiO2; dichloromethane:methanol (95:5)] to give exo-3-(5-(2.2.2-trifluoroethoxv)pvrid-3-vl)-endo-3-cyano-8-methyl-8azabicyclo[3.2.1]octane (0.065g, 80% pure).
EXAMPLE 81
This example illustrates the preparation of exo-3-(5-chloropyrid-3-yI)-endo-3-cyano-8-( 1 cyanoethyl)-8-azabicyclo[3.2.1]octane.
exo-3-(5-Chloropyrid-3-yn-endo-3-cyano-8-azabicyclor3.2.1]octane (0.50g), 2bromopropionitrile (2ml) and potassium carbonate (0.50g) were refluxed in ethanol (5ml). After 24 hours the mixture was cooled to room temperature, water added and the mixture extracted with dichloromethane (x3). The combined extracts were washed with brine, dried (MgSO4) and evaporated under reduced pressure. Chromatography [SiO2; dichloromethane-.methanol (100:0) to (98:2)] followed by chromatography [SiO2; ethyl acetate:hexane (80:20)] and preparative thin layer chromatography [A12O3; ethyl acetate:hexane (40:60)] gave exo-3-(5-chloropyrid-3-yl)-endo-3-cyano-8-(l-cyanoethyl)-815 azabicyclo[3.2.1]octane (0.044g, 80% pure).
EXAMPLE 82
This example illustrates the preparation of exo-3-(5-phenylpyrid-3-yI)-endo-3-cyano-8(vinyloxy carbonyl)-8-azabicyclo[3.2.1 ]octane.
Vinyl chloroformate (2.17ml) was added a solution of exo-3-(5-iodopyrid-3-yl)-endo-3ί 20 cyano-8-methyl-8-azabicyclo[3.2.1]octane (3.0g) in tetrahydrofuran (20ml) at 0°C. The mixture was then heated under reflux for 5 hours and then stand at room temperature overnight. Water was then added and the mixture extracted with dichloromethane (x3). The combined extracts were washed with water and brine, dried (MgSO4) and evaporated under reduced pressure. Chromatography [SiO2; dichloromethane:methanol (98:2)] gave exo-3-(525 iodopyrid-3-yl)-endo-3-cyano-8-(vinyloxycarbonyl)-8-azabicyclo[3.2.1 ]octane (3.64g).
Tetrakis(triphenylphosphine)palladium(0) (0.042g) was added to a stirred solution of exo-3(5-iodopyrid-3-yl)-endo-3-cyano-8-(vinyloxycarbonyl)-8-azabicyclo[3.2. l]octane (0.50g) in toluene (2ml). To this mixture was added 2M sodium carbonate solution (1.22ml) and phenylboronic acid (0.16g) in ethanol (0.5ml) and the mixture heated under reflux. After 2 hours the mixture was cooled to room temperature, water added and the mixture extracted with ethyl acetate (x3). The combined extracts were washed with brine, dried (MgSO4) and evaporated under reduced pressure. Chromatography [SiO2; ethyl acetate:hexane (45:55)]
AP/P/ 9 7/01139 gave exo-3-(5-phenylpyrid-3-yl)-endc>-3-cyano-8-(viiiyloxycarbonyl)-8azabicyclo[3.2.1]octane (O.33g).
EXAMPLE 83
This example illustrates the preparation of exo-3-(5-phenylpyrid-3-yl)-endo-3-cyano-8azabicyclo[3.2.1 ] octane.
Concentrated hydrochloric acid (0.5ml) was added to a solution of exo-3-(5-phenylpvrid-3yl)-endo-3-cyano-8-(vinyloxycarbonyl)-8-azabicyclo[3.2.1]octane (0.30g) in methanol (10ml) and the mixture heated under reflux. After 5 hours the mixture was allowed to stand at room temperature for 4 days and then heated under reflux for 5 hours. The mixture was then allowed to cool to room temperature, basified with saturated sodium bicarbonate solution and extracted with dichioromethane (x3). The combined extracts were washed with brine and <; ? extracted with 2M hydrochloric acid (x2). The acidic extracts were basified and re-extracted with dichioromethane (x3). The combined organic extracts were washed with brine, dried (MgSO4) and evaporated under reduced pressure to give exo-3-(5-phenylpyrid-3-yl)-endo-3cyano-8-azabicyclo[3.2.1]octane (0.20g).
EXAMPLE 84
This example illustrates the preparation of exo-3-(5-methylpyrid-3-yl)-endo-3-cyano-8(vinyloxycarbonyl)-8-azabicyclo[3.2.1]octane.
Methyllithium (8.7ml of a 1.4M solution in diethyl ether) was added dropwise to a stirred suspension of copper(I) iodide (1.16g) in diethyl ether (10ml) at 0°C under nitrogen. After 45 minutes exo-3-(5-iodopyrid-3-yl)-endo-3-cyano-8-(vinyloxvcart?onvl)-8- .
azabicyclo[3.2.1]octane (0.50g) in diethyl ether (5ml) was added. After 5 days at room temperature water was added and the mixture extracted with ethyl acetate (x3). The combined extracts were washed with brine, dried (MgSO4) and evaporated under reduced pressure. Chromatography [SiO2; ethyl acetate:hexane (60:40)] gave exo-3-(5-methvlpyrid3-yl)-endo-3-cyano-8-(vinyloxycarbonyl)-8-azabicyclo[3.2.1]octane (0.085g).
EXAMPLE 85
This example illustrates the preparation of exo-3-(5-chloropyrid-3-yl)-endo-3-cyano-8-(2cyanoprop-2-yl)-8-azabicyclo[3.2.1 ]octane.
Sodium cyanide (0.069g) was added to a stirred solution of exo-3-(5-chloropyrid-3-vl)-endo3-cyano-8-isopropylene-8-azabicyclo[3.2.1]octanium perchlorate (0.50g) in acetonitrile (5ml) at room temperature under nitrogen. After 4 hours the mixture was allowed to stand at room table.
EXAMPLE . 2 , , 4
AP.00803
- 57 temperature over the weekend, water added and the mixture extracted with dichloromethane (x3). The combined extracts were washed with brine, dried (MgSO4) and evaporated under reduced pressure to give exo-3-(5-chloropyrid-3-yl)-endo-3-cyano-8-(2-cyanoprop-2-yl)-8azabicyclo[3.2.1]octane (0.38g, 90% pure).
EXAMPLE 86
This example illustrates the preparation of exo-3-(5-(ethoxycarbonyl)pyrid-3-yl)-endo-3cyano-8-(vinyloxycarbonyl)-8-azabicyclo[3.2.1]octane.
Potassium carbonate (0.205g) and bis(triphenylphosphine)paUadium(IT) chloride (0.026g) were added to a stirred solution of exo-3-(5-iodopyrid-3-yl)-endo-3-cyano-8-methyl-810 azabicyclo[3.2.1]octane (0.50g) in ethanol (10ml) under nitrogen. The reaction vessel was then flushed with carbon monoxide, triethylamine (3 drops) added and the mixture heated under reflux. After 3 hours the mixture was cooled to room temperature, water and brine added and the mixture extracted with ethyl acetate (x3). The combined extracts were dried (MgSO4), evaporated under reduced pressure and chromatographed [SiO2; ethyl acetate:hexane (35:65)] to give exo-3-f 5-( ethoxycarbonyPpyrid-S-yP-endo-S-cyano-S(vinyloxycarbonyl)-8-azabicyolo[3.2. l]octane (0.29g).
Confirmation of the structural identity of the compounds prepared in Examples 20 to 106 was obtained by proton magnetic resonance spectroscopy. The results are set out in the following ’H NMR (270MHz), in CDCI3 unless otherwise stated
8.81 (1H, d), 8.56 (1H, dd), 7.85 (1H, dt), 7.30 (1H, dd), 3.44 (2H, m), 2.45-2.15 (8H, m) and 2.33 3H, s).
8.80 (1H, d), 8.55 (1H, dd), 7.85 (1H, m), 7.30 (1H, m), 4.55 (2H, dt), 3.4 (2H, m), 2.70 (2H, dt) and 2.4-2.1 (8H, m).
7.09 (2H. m), 6.75 (1H, m). 3.31 (2H, m), 2.4-2.1 (8H, m) and 2.35 (3H. s).
8.80 (1H, d), 8.54 (1H, dd), 7.83 (1H, dt), 7.29 (1H, dd), 3.40 (2H, m). 2.4-2.0 (10H, m),
1.48 (2H, hex) and 0.91 (3H, s).
7.53 (2H, m), 7.4-7.2 (8H, m), 3.59 (2H, s), 3.36 (2H, m) and 2.5-2.15 (8H, m).
8.82 (1H. d), 8.58 (1H, dd), 7.86 (1H, dt), 7.4-7.2 (6H, m), 3.59 (2H. s), 3.39 (2H, m) and 2.45-2.15 (8H, m).
8.80 (1H, d). 8.56 (1H, dd), 7.84 (1H, dt), 7.31 (1H, dd), 3.50 (2H, t), 3.48 (2H, m), 3.36 (3H, s). 2.61 (2H, t) and 2.4-2.05 (8H, m).
8.94 (1H, d), 8.59 (1H, t), 8.53 (1H, d), 3.35 (2H, m), 2.65-2.55 (2H, m), 2.4-2.1 6H, m) and 2.36 (3H, m).
AP/P/97/0 1 1 39
8.82 (1H, s), 8.54 (1H, s), 3.37 (2H, m), 2.54 (2H, dd), 2.4-2.1 (BH, m) and 2.35 (3H, s).
7.78 (1H, d), 7.55 (1H, d), 3.40 (2H, m), 2.70 (2H, m), 2.5-2.1 (6H, m) and 2.37 (3H, s).
8.49 (1H, d), 7.95 (1H, d), 3.34 (2H, m), 2.4-2.15 (8H, m) and 2.35 (3H, s).
8.81 (1 H, d), 8.56 (1H, dd), 7.84 (1H, dt), 7.31 (1H, dd), 3.72 (3H, s), 3.50 (2H, m), 3.22 (2H, s), 2.5-2.3 (6H, m) and 2.2-2.1 (2H, m).
8.89 (1H, d), 8.60 (1H, dd), 7.87 (1H, dt), 7.35 (1H, dd), 4.54 (2H, m), 4.50 (2H, s), 3.22 (3H, s) and 2.6-2.25 (3H, m).
8.59 (1H, d), 7.31 (1H, dd), 7,34 (1H, d), 2.33 (2H, m) 2.4-2.15 (8H, m) and 2.35 (3H, s).
8.89 (1H, d), 8.51 (1H, d), 7.82 (1H, t), 3.42 (2H, m), 2.4-2.0 (10H, m), 1.5-1.2 (SH, m) and 0.89 (3H, m).
5.70 (1 H, d), 8.52 (1H, d), 7.83 (1H, t), 5.88 (1H, m), 5.18 (2H, m), 3.42 (2H, m), 3.02 (2H, m) and 2.4-2.05 (8H, m).
8.70 (1H, d), 8.55 (1H, d), 7.80 (1H, t), 3.50 (2H, m), 2.90 (2H, q), 2.5-2.2 (6H, m) and 2.10 (2H, m).
8.74 (1H, d), 8.61 (1H,'d), 8.00 (1H, t), 3.35 (1H, m), 2.4-2.15 (8H, m) and 2.33 (3H, s).
9.03 (1H, d), 8.82 (1H, d), 8.15 (1H, t), 3.36 (1H, m), 2.4-2.2 (8H, m) and 2.35 (3H, s).
8.40 (1H, d), 8.21 (1H. d), 7.34 (1H, t), 4.10 (2H, q), 3.31 (2H, m), 2.4-2.15 (8H, m), 2.32 (3H, s) and 1.44 (3H, t).
8.70 (1H, d), 8.50 (1H, d), 7.80 (1H, t), 3.70 (2H, m), 2.65 (1H, m), 2.35 (2H, m), 2.25 (4H, m), 2.05 (2H, m) and 1.05 (6H, d).
7.47 (2H, s), 3.32 (2H, m), 2.35-2.15 (8H, m) and 2.32 (3H, s).
8.39 (1H, d), 7.51 (1H, d), 7.40 (1H, dd), 3.32 (2H, m), 2.4-2.1 (8H, m) and 2.32 (3H, s).
8.61 (2H, m), 7.49 (2H, m), 3.33 (2H, m), 2.4-2.1 (8H, m) and 2.32 (3H, s).
8.69 (1H, d), 8.51 (1H, d), 7.81 (1H, t), 4.35 (1H, ddt), 3.41 (2H, m), 3.00 (2H, dt) and 2.42.1 (8H, m).
8.59 (2H. m), 7.98 (1H, d), 7.72 (1H, d), 5.55 (1H, d), 4.36 (1H, m), 4.25 (1H, m), 2.7-2.2 (8H, m).
8.65 (1H, d), 8.55 (1H, d), 7.75 (1H, t), 4.95 (1H, m), 4.40 (1H, m), 2.65-2.1 (8H, m) and 2.15 (3H,s).
[in DMSO] 8.79 (1H, brs), 8.70 (1H, d), 8.64 (1H, brs), 8.61 (1H, d), 4.16 (2H, m), 2.7-2.6 (2H, m), 2.45-2.25 (4H, m), and 2.15-2.0 (2H, m).
8.67 (1H, d), 8.49 (1H, d), 7.80 (1H, t), 3.79 (2H, m), 2.4-2.15 (SH, m), 2.0-1.9 (2H, m) and 1.09 (9H, s).
8.69 (1H, d), 8.52 (1H, d), 7.82 (1 H, t). 7.54 (2H, m), 7.4-7.25 (3H, m), 3.90 (1 H, m), 3.70 (1H. d), 3.65 (1H, d), 3.31 (1H, m), 2.5-2.0 (8H, m) and 1.49 (3H, m).
8.60 (1H, d), 8.50 (1H, d), 7.71 (1H, t). 7.4-7.25 (5H, m), 3.40 (1H, m), 3.32 (1H, m), 2.82 (1H, t), 2.66 (1H, t), 2.3-1.95 (8H, m) and 1.74 (3H, d).
8.70 (1H, d), 8.54 (1H, d), 7.85 (1H. t), 7.50 (2H, m), 7.4-7.25 (3H, m), 4.31 (1H, d),4.19 (1H, d), 3.85 (IH, m), 2.34 (1H, m), 2.5-2.15 (8H, m), 2.00 (3H, s) and 1.56 (3H, s).
AP.ύ ο β ο 3
- 59 36 8.64 (1 Η, d), 8.56 (1 Η, d), 8.20 (1 Η, s), 7.77 (1 Η, t), 4.86 (1 Η, m), 4.32 (1Η, m) and 2.62.1 (8Η, m).
8.69 (1H, d), 8.52 (1H, d). 7.85 (1H,-1), 4.11 (2H, m). 3.65 (2H, hept), 2.55-2.1 (8H, m) and
1.30 (12H, d).
8.62 (1H, d), 8.52 (1H, d), 7.75 (1H, t), 4.26 (2H, m), 2.5-2.15 (8H, m) and 1.40 (9H, s).
8.71 (1H, d), 8.53 (1H, d), 7.84 (1H, t), 7.4-7.2 (5H, m), 3.71 (1H, m), 3.49 (1H, q), 3.28 (1H, m), 2.4-2.05 (8H, m) and 1.30 (3H, d).
8.20 (1H, d), 8.00 (1H, d), 7.11 (1H, t), 3.76 (2H, brs), 3.32 (2H, m), 2.4-2.1 (8H, m) and 2.32 (3H, s).
8.62 (1H, d), 8.56 (1 H, d), 8.22 (1H, t), 7.46 (1H, brs), 3.35 (2H, m), 2.4-2.2 (8H, m), 2.35 (3H, s) and 2.21 (3H, s).
8.69 (1H, d), 8.54 (1H, d), 7.81 (1H, t), 7.55-7.35 (5H, m), 4.38 (1H, s), 3.94 (1H, m), 3.29 (1H, m) and 2.6-2.1 (8H. m).
8.69 (1H, d), 8.55 (1H, d), 7.81 (1H, t), 7.45-7.3 (5H, m), 6.91 (1H, m), 5.70 (1H, m), 3.96 (1H, s), 3.60 (1H, m), 3.35 (1H, m), 2.5-2.2 (6H, m) and 2.05-1.9 (2H, m).
8.77 (2H, m), 8.16 (1H, t), 3.32 (2H, m), 2.4-2.1 (8H, m) and 2.32 (3H, s).
9.02 (1H, d), 8.83 (1H, m), 8.07 (1H, m), 3.36 (2H, m) and 2.4-2.05 (11H, m).
[in DMSO] 8.72 and 8.62 (1H, m), 8.58 (1H, m), 8.14 and 7.86 (1H, m), 5.39 (1H, m), 4.20 (1H, m) 2.7-2.0 (8H, m).
8.65 (1H, d), 8.58 (1H, d), 7.78 (1H, t), 4.51 (2H, m), 2.6-2.2 (8H, m).
*
8.69 (1H, d), 8.52 (1H, d), 7.81 (1H, t), 5.85 (1H, tt), 3.45 (1H, m), 2.71 (2H, dt) and 2.52.0 (8H, m).
8.69 (1H, d), 8.52 (1H. d), 7.82 (1H, t), 7.35-7.15 (5H, m), 3.45 (2H, m), 2.79 (2H, m),
2.61 (2H, m) and 2.4-2.05 (8H, m).
8.39 (1H, m), 8.05 (1H, m), 7.59 (1H, m), 3.43 (2H, m) 2.5-2.1 (8H, m) and 2.40 (3H, s).
8.70 (1H, d), 8.52 (1H, d), 7.83 (1H, t), 7.4-7.2 (5H, m), 3.57 (2H, s), 3.40 (2H, m) and
2.45-2.2 (8H, m).
8.63 (1H, d), 8.50 (1H, d), 7.77 (1H, t), 3.60 (2H, m), 3.42 (2H, m) and 2.5-2.2 (8H, m).
8.71 (1H, d), 8.53 (1H, d), 8.10 (1H, t), 7.90 (2H, m), 7.39 2H, m), 3.45 (2H, m), 3.30 (2H,
m) and 2.4-2.2 (8H,m).
8.69 (1H, d), 8.53 (1H, d), 7.83 (1H, t), 7.42 (1H, dd), 7.22 (1H, m), 7.09 (1H, t), 3.50 (2H, s), 3.36 (2H, m) and 2.45-2.15 (8H, m).
8.71 (1H, d), 8.52 (2H, m), 7.86 (1H, t), 7.69 (1H, dt), 7.54 (1H, d), 7.19 (1H, m), 3.73 (2H,s), 3.43 (2H, m) and 2.5-2.2 (8H, m).
8.70 (1H, d), 8.52 (1H, d), 7.85 (1H, t), 7.00 (1H, s), 3.66 (2H, s), 3.49 (2H, m), 2.70 (3H, s) and 2.45-2.15 (8H, m).
6.61 (1H, d), 8.52 (1H, d), 7.78 (1H, t), 3.33 (2H, m), 3.29 (2H, s), 2.5-2.1 (8H, m), 2.38 (3H, s) and 2.32 (3H, s).
8.70 (1H, d), 8.52 (1H, d), 7.83 (1H, t), 6.74 (1H, d), 6.65 (1H, d), 3.65 (2H, s), 3.46 (2H, m) and 2.45-2.1 (8H, m).
8.65 (1H, d), 8.50 (1H, d), 7.80 (1H, t), 3.94 (2H, s), 3.55 (2H, m) and 2.5-2.25 (8H, m).
8.65 (1H, d), 8.41 (1H, d), 7.60 (1H, dt), 3.44 (2H, m), 2.4-2.15 (8H, m) and 2.35 (3H, s).
8.69 (2H, m), 7.84 (1H, t), 7.10 (2H, m), 6.40 (2H, m), 3.34 (2H, m), 2.4-2.15 (8H, m) and
2.33 (3H, s).
AP/P/ 9 7/01 139
- 60 62 8.79 (1 Η, d), 8.75 (1 Η, d), 8.05 (1 Η, m). 4.74 (1 Η, d), 4.31 (1 Η, d). 3.94 (2Η, q), 3.40 (2Η, m), 2.5-2.2 (11H, m) and 1.44 (3H, t).
9.09 (1H, d), 8.99 (1H, d), 8.39 (1H, t), 3.37 (2H, m), 2.69 (3H, s), 2.45-2.15 (8H, m) and
2.34 (3H, s).
8.76 (1H, d), 8.62 (1H, d), 7.94 (1H, m), 3.34 (2H, m), 3.24 (1H, s), 2.45-2.15 (8H. m) and
2.35 (3H, s).
8.80 and 8.70 (1H, m), 8.29 {1H, m), 7.95 (1H, m), 7.71 (1 Hm), 7.56 (1H, m), 7.4-7.1 (3H, m), 5.65 and 5.29 (1H, m), 4.91 and 4.75 (1H, m), 4.30 and 4.11 (1H, m), 3.30 (1H, m), 2.8-2.0 (8H, m) and 1.73 and 1.62 (3H, m).
8.61 (1H, d), 8.52 (1H,d), 7.79 (1H, t), 7.5-7.15 (5H, m), 3.01 (1H, m), 2.91 (1H, m), 2.79 (1H, m), 2.39 (2H. m), 2.3-1.6 (12H, m), 1.09 (3H, d) and 0.91 (3H, d).
8.69 (1H, d), 8.52 (1H, d), 7.81 (1H, 1), 3.55 (2H, m), 3.35 (2H, s) and 2.5-2.1 (8H, m).
8.69 (1H, d), 8.52 (1H, d), 7.81 (1H, t), 4.20 (2H, m), 3.61 (1H, m), 3.49 (1H, m), 3.23 (1H, q), 2.45-2.0 (8H, m), 1.31 (3H, d) and 1.29 (3H, t).
8.50 (1H, d), 8.35 (1H, d), 7.7-7.5 (2H, m), 6.40 (2H, dd), 6.25 (1H, dd), 4.70 (2H, m), 2.62.5 (2H, m) 2.45-2.20 (6H, m).
8.51 (1H, d), 8.49 (1H, d), 7.70 (1H, t). 4.45 (2H, m), 2.6-2.5 (4H,m) and 2.4-2.2 (4H, m).
8.70 (1H, d), 8.55 (1H, d), 7.85 (1H, t), 4.25 (2H, m) and 2.6-2.2 (8H, m).
8.29 (1H, d), 8.10 (1H, d), 7.90 (1H, m), 4.15 (2H, m) 2.6-2.25 <8H, m).
8.75, 8.65 and 8.50 (1H, m), 7.90 and 7.80 (1H, m), 3.80 and 3.70 (2H, m), 3.6 and 3.5 (3H, m) and 2.7-1.8 (8H, m).
8.65 (1H, d), 8.51 (1H, d), 7.80 (1H, t), 4.16 (2H, q), 3.41 (2H, m), 2.69 (2H, t), 2.48 (2H, t), 2.4-2.05 (8H, m) and1.27 (3H, t).
8.76 (1H, m), 8.52 (1H, m), 7.98 (1H, m), 3.85 (2H, m), 3.01 (2H, t), 2.8-2.2 (1 OH, m).
8.64 (1H, d), 8.51 (1H, d), 7.80 (1H, t), 4.18 (4H, m), 3.60 (2H, m), 2.78 (2H, d), 2.45-2.05 (8H, m) and 1.36 (6H, m).
[in DMSO] 8.89 (1H, d), 8.62 (1H, d), 8.29 (1H, t), 4.50 (2H, m), 3.48 (2H, d) and 2.852.45 (8H, m).
8.69 (1H, d), 8.51 (1H, d), 7.80 (1H, t), 3.46 (2H, m), 2.64 (2H, m), 2.51 (2H, m) and 2.452.0 (8H, m).
9.65 (1H, d), 8.51 (1H, d), 7.79 (1H, t), 3.91 (2H, m), 2.45-2.2 (8H, m) and 1.28 (6H, s).
8.55 (1H, d), 8.3 (1H, d) 7.45 (1H, t), 3.35 (2H, m), 2.4-2.1 (8H, m) and 2.3 (3H, s).
8.69 (1H, d), 8.52 (1H, d), 7.81 (1H, t), 3.85 (1H, m), 3.60 (1H, m), 3.50 (1H, q), 2.5-2.1 (8H, m) and 1.51 (3H, d).
8.81 (1H, d), 8.71 (1H, d), 7.92 (1H, t), 7.6-7.35 (5H, m), 7.25 (1H, dd), 4.80 (1H, dd), 4.61 (2H, m), 4.49 (1H, dd) and 2.55-2.15 (8H, m).
8.79 (2H, m), 7.99 (1H, t), 7.6-7.35 (5H, m), 3.75 (2H, m), 2.55-2.2 (6H, m) and 2.05-1.85 (2H, m).
8.55 (1H, m), 8.40 (1H, m), 7.55 (1H, m), 7.23 (1H, dd),4.80 (1H, dd), 4.59 (1H, m), 4.49 (1H, dd), 2.6-2.1 (8H, m) and 2.39 (3H, s).
8.64 (1H, d), 8.52 (1H, d), 7.70 (1H, t), 3.91 (1H, m), 2.55-215 (8H, m) and 1.52 (6H, s).
9.19 (1H, d), 8.90 (1H, d), 8.31 (1H, t), 7.24 (1H, dd), 4.82 (1H, dd), 4.63 (2H, m), 4.51 (1H, dd), 4.44 (2H, q), 2.6-2.2 (8H, m) and 1.43 (3H, t).
AP. 0080 J
- 61 EXAMPLE 87
This Example illustrates an emulsifiable concentrate composition which is readily convertible by dilution with water into a liquid preparation suitable for spraying purposes. The concentrate has the following composition:
% Weight
Compound No. 1 25.5
SYNPERONIC NP13 2.5
Calcium dodecylbenzenenesulphonate 2.5
AROMASOLH 70
A- ) EXAMPLE 88
This Example illustrates an emulsifiable concentrate composition which is readily convertible by dilution with water into a liquid preparation suitable for spraying purposes. The concentrate has the following composition:
% Weight
Compound No.5 50.0
SYNPERONIC NP13 6.0
Calcium dodecylbenzenesulphonate 4.0
AROMASOL H 40.0
Viji?
EXAMPLE 89
This Example illustrates an emulsifiable concentrate composition which is readily convertible by dilution with water into a liquid preparation suitable for spraying purposes. The concentrate has the following composition:
AP/P/ 9 7/01139
Compound No.9 % Weight 1.0
SYNPERONIC OP10 3.0
Calcium dodecylbenzenesulphonate 2.0
AROMASOL H 94.0
EXAMPLE 90
This Example illustrates a wettable powder composition which is readily convertible by dilution with water into a liquid preparation suitable for spraying purposes. The wettable powder has the following composition:
Compound No. 13 % Weight 25.0
Silica 25.0
Sodium lignosulphonate 5.0
Sodium lauryl sulphate 2.0
Kaolinite 43.0
EXAMPLE 91
This Example illustrates a wettable powder composition which is readily convertible by dilution with water into a liquid preparation suitable for spraying purposes. The wettable powder has the following composition:
Compound No. 17 % Weight 1.0
Sodium lignosulphonate 5.0
Sodium lauryl sulphate 2.0
Kaolinite 92.0
EXAMPLE 92
This Example illustrates a wettable powder composition which is readily convertible by dilution with water into a liquid preparation suitable for spraying purposes. The wettable power has the following composition:
Compound No.21 % Weight 40.0
Silica 40.0
Calcium lignosulphonate 5.0
Sodium lauryl sulphate 2.0
Kaolinite 13.0
EXAMPLE 93
This Example illustrates a dusting powder which may be applied directly to plants or other surfaces and comprises 1% by weight of Compound No.25 and 99% by weight of talc.
AP.00803
- 63 EXAMPLE 94
This Example illustrates a concentrated liquid formulation suitable for application by ultra low volume techniques after mixing with paraffinic diluents.
% Weight
Compound No.29 90.0
SOLVESSO 200 10.0
EXAMPLE 95
This Example illustrates a concentrated liquid formulation suitable for application by ultra low volume techniques after mixing with paraffinic diluents.
% Weight
Compound No.33 25.0
SOLVESSO 200 75.0
EXAMPLE 96
This Example illustrates a concentrated liquid formulation suitable for 15 application by ultra low volume techniques after mixing with paraffinic diluents.
% Weight
Compound No.37 10.0
SOLVESSO 200 90.0
EXAMPLE 97
This Example illustrates a liquid formulation suitable for application (undiluted) by ultra low volume techniques.
AP/P/ 97 / 0 1139 % Weight
Compound No.41 15
Cotton seed oil 50
SOLVESSO 200 35
EXAMPLE 98
This Example illustrates a capsule suspension concentrate which is readily convertible by dilution with water to form a preparation suitable for application as an aqueous spray.
Compound No.45 % Weight 10.0
- 64 Alkylbenzene solvent (e.g. AROMASOL H) 5.0
Toluene di-isocyanate 3.0
Ethylenediamine 2.0
Polyvinyl alcohol 2.0
Bentonite 1.5
Polysaccharide (e.g. KELTROL) 0.1
Water 76.4
EXAMPLE 99
This Example illustrates a capsule suspension concentrate which is readily 10 convertible by dilution with water to form a preparation suitable for application as an aqueous spray.
% Weight r Compound No.49 1.0
Alkylbenzene solvent (e.g. AROMASOL H) 10.0
Toluene di-isocyanate 3.0 t
Ethylenediamine 2.0
Polyvinyl alcohol 2.0
Bentonite 1.5
Polysaccharide (e.g. KELTROL) 0.1
Water 80.4
EXAMPLE 100
A ready for use granular formulation:
Compound No.4 % Weight 0.5
25 SOLVESSO 200 0.2
nonylphenol ethoxylate 0.1
(eg Synperonic NP8)
Calcium carbonate granules 99.2
(0.3-0.7 mm)
EXAMPLE 101
An aqueous suspension concentrate:
% Weight
AP.0 08 0 3
Compound No.8 5.0
Kaolinite 15.0
Sodium lignosulphonate 3.0
nonylphenolethoxylate (eg Synperonic NP 8) 1.5
propylene glycol 10.0
Bentonite 2.0
Polysaccharide (eg Keltrol) 0.1
Bactericide (eg Proxel; Proxel is a registered Trade Mark) 0.1
Water 63.3 EXAMPLE 102
A ready for use dust (D.P.) made from a concentrate Concentrate: % Weight
Compound No.12 10
Silica 20
Magnesium Carbonate 70
Dust Example containing 1% active ingredient:
Above concentrate 10
Talc 90 EXAMPLE 103
This Example illustrates a ready for use granule formulaton. % Weight
Compound No. 16 5
Synperonic NP8 2
AP/P/ 9 7/0113»
Pumice granules (20/40 BS Mesh) 93
EXAMPLE 104
This Example illustrates a water dispersible granule formulation.
% Weight
Ί**
Compound No.20 5
Silica 5
Sodium lignosulphate 10
Sodium dioctylsulphosuccinaie 5
Sodium acetate 10
Montmorillonite powder 65
EXAMPLE 105
This Example illustrates the insecticidal properties of the compounds of Formula I. The activity of the the compounds of Formula I was determined using a variety of pests. The pests were treated with a liquid composition containing 500 parts per million (ppm) by weight of the compound unless otherwise stated. The compositions were made by dissolving the compound in .. acetone and ethanol (50:50) mixture and diluting the solutions with water containing 0.05% by weight of a wetting agent sold under the trade name SYNPERONIC NP8 until the liquid composition contained the required concentration of the compound. SYNPERONIC is a
Registered Trade Mark.
The test procedure adopted with regard to each pest was basically the same and comprised supporting a number of the pests on a medium which was usually a substrate, a host plant or a foodstuff on which the pests feed, and treating either or both the medium and the pests with the compositions. The mortality of the pests was then assessed at periods usually varying from two to five days after the treatment.
The results of the tests against peach aphid (Myzus persicae) are presented in Table Π. The results indicate a grading of mortality (score) designated as A, B or C wherein C indicates less than 40% mortality, B indicates 40-79% mortality and A indicates 80-100% mortality; indicates that either the compound was not tested or no meaningful result was obtained. In this test Chinese cabbage leaves were infested with aphids, the infested leaves were sprayed with the test composition, and the mortality assessed after 3 days.
Information regarding the pest species, the support medium or food, and the type and duration of the test is given in Table EQ. The pest species is designated by a letter code.
AP .9080 3
- 67 TABLED
Nil*/ . i'-d
Comp’d No Score Comp’d No Score Comp’d No Score Comp'd No Score
1 A 2 A 3 A 4 A
5 A 6 C 7 C 8 A
9 A 10 A 11 A 12 A
13 B 14 A 15 A 16 C
17 C 18 A 19 C 20 C
21 A 22 A 23 A 24 A
25 A 26 B 27 A 28 C
29 B 30 A 31 C 32 A
33 A 34 A 35 A 36 A
37 A 38 A 39 C 40 A
41 A 42 A 43 A 44 A
45 C 46 A 47 A 48 A
49 A 50 A 51 A 52 C
53 A 54 A 55 A 56 A
57 A 58 C 59 A 60 A
61 A 62 A 63 C 64 A
65 C 66 C 67 A 68 A
69 A 70 A 71 A 72 A
73 C 74 A 75 A 76 A
77 A 78 A 79 A 80 A
81 A 82 A 83 A 84 A
85 A 86 A 87 A 88 A
89 C 90 A 91 A 92 A
93 A 94 C 95 A 96 A
97 C 98 A 99 A 100 A
101 A 102 A 103 A 104 A
105 B 106 A 107 A 108 A
AP/P/ 9 7 / 0 1 1 3»
A 110 A 111 A 112 B
A 114 A 115 A 116 A
A 118 A 119 A 120 A
A 122 A 123 A 124 A
A 126 C 127 - 128 A
A 130 A 131 A 132 A
A 134 · A 135 A 136 C
C 138 A 139 A 140 A
A 142 A 143 A 144 A
A 146 A 147 A 148 B
A 150 A 151 A 152 A
A 154 B 155 A 156 A
C 158 A 159 A 160 A
A 162 C 163 C 164 A
A 166 A 167 A 168 A
A 170 B 171 A 172 A
A 174 A 175 A 176 A
A 178 A 179 A 180 A
A 182 A 183 A 184 A
A 186 A 187 C 188 A
A 190 - 191 A 192 A
A 194 A 195 A 196 A
A 198 A 199 A 200 A
A 202 A 203 A 204 A
A 206 A 207 A 208 A
A 210 A 211 A 212 A
A 214 A 215 A 216 -
A 218 A 219 - 220 A
A 222 C 223 C 224 -
A 226 - 227 A 228 A
A 230 A 231 A 232 A
A 234 A 235 A 236 A
AP. 0 0 8 0 3
237 241 246 A A A 238 242 247 A A A 239 243 248 A A A 240 245 249 A' ' A A
254 A 255 A 256 A 257 A
258 A 259 A 260 A 261 A
262 A 263 A 264 A 265 A
266 A 267 A 268 A 269 A
270 A 271 A 272 A 273 A
274 A 275 A 276 A 277 A
278 A 279 A 280 A 281 A
282 A 283 A 284 A 285 A
286 A 287 A 288 A 289 A σ*
290 A 291 - 292 A 293 A IO
294 A 295 - 296 A 297 A -r-
298 A 299 A 300 A 301 A
302 A 303 - 304 A 305 - r*.
306 - 307 - 308 - 309 A er>
310 A 311 A 312 A 313 A C*~
314 A 315 A 316 A 317 A £ <
318 A 319 A 320 A 321 A
In tests against tobacco budworm (Heliothis virescens. larvae) the following compounds scored A or B.
Compounds 2, 8, 14, 18, 23, 66, 72, 95, 99, 102, 104, 120, 131, 156, 169, 170, 227, 229, 231,
234, 236, 243,260,262, 270, 274, 312.
k s
In tests against root knot nematodes (Meloidogvme incognita') the following compounds scored A or B.
Compounds 36, 55. 71, 77, 94, 99, 120, 160, 207, 233, 237, 238, 253, 257, 271, 312, 317, 318. In tests against red spider mite (Tetranvchus urticae) the following compounds scored A or B.
Compounds 12,13, 22, 23, 25, 34, 37, 39, 47, 53, 63, 64, 66, 87, 90, 99, 101, 106,120,135,
142, 186, 193, 195, 199, 201, 207, 208, 236, 237, 239, 245, 247, 249, 280, 283, 310 to 321.
In tests against Whitefiy fBemesia tabacri the following compounds were particularly effective. Compounds 33, 34, 36, 56, 64, 68, 69, 70, 72, 74, 76, 77, 81, 90, 93, 99, 227 to 275.
The chemical formulae referred to in the preceding description are set out below.
AP. Ο Ο 8 Ο 3

Claims (17)

1. A compound of formula (I);
R2 wherein R1 represents a group of formula (A)
Y^ where each of W, X, Y and Z represents either a group CR or the nitrogen atom, provided that not more than two of W, X, Y and Z represent the nitrogen atom and where each R present is independently selected from hydrogen and halogen atoms and cyano, amino, hydrazino, acylamino, hydroxy, alkyl, hydroxvalkvl, alkoxy, haloalkyl, haloalkoxy, alkenyl, alkenyloxy, alkoxyalkenyl, alkynyl, carboxylic acyl, alkoxvcarbonyl, aryl and heterocyclyl groups, said groups comprising up to 6 carbon atoms, and wherein R2 represents hydrogen or cyano or a group selected from alkyl, aryl, heteroaryl, aralkyl, heteroarylalkyl, alkenyl, aralkenyl, alkynyl, alkoxvcarbonyl, alkanesulfonyl, arenesulfonyl, alkanyloxycaibonyl, aralkyloxycarbonyl, aryloxycarbonyl, heterocyclylalkyl, carbamyl or dithiocarboxyl groups, said groups comprising from 1 to 15 carbon atoms, said groups being optionally substituted with one or more substituents selected from, halogen, cyano, carboxyl, carboxylic acyl, carbamyl, alkoxvcarbonyl, alkoxy, alkylenedioxy, hydroxy, nitro, haloalkyl, alkyl, amino, acylamino, imidate and phosphonato groups; and acid addition salts, quaternary ammonium salts and N-oxides derived therefrom;
AP. Ο Ο 8 Ο 3
- 72 a and when R1 is 5-chloropyrid-3-yl R2 may also be: acetyl, trifluoroacetyl, 4-chlorobenzoyl, 4fluorobenzoyl, formyl, fluorocarbonyl, N-methyl-N-phenylcarbamyl, 4-morpholinocarbonyl, N(3-chloro-4-fluorophenyl)carbamyl, 4-allyl-
2,3,5,6-tetrafluorobenzyl, 3-trifluoromethoxybenzyl, 2-(N-succinimido)benzyl, 4-l,2,3-thiadiazol-4-yl)benzyl, 3-(4-fluorophenoxy)benzyl, 2phenoxyethyl, cyclohexylmethyl, methoxy or methylmercaptothiocarbonyl; provided that R1 is not unsubstituted phenyl when R2 is unsubstituted benzyl or tosyl.
AP/P/ 9 7/01 139
AP. Ο Ο 8 Ο 3
- 73 2. A compound according to claim 1 wherein R1 represents a halo-substituted phenyl, pyridyl or diazinyl group.
3. A compound according to claim 1 where R1 represents an optionally halogen
5 substituted phenyl group or an optionally halogen substituted pyridyl, pyridazinyl or pyrazinyi group and R2 represents hydrogen or a alkyl, alkenyl, alkynyl, phenyl, benzyl, pyridylmethyl, thienylmethyl or thiazolylmethyl group which may be optionally substituted with one or more alkyl, alkoxy, alkoxycarbonyl, cyano, optionally substituted alkane sulphonyl groups or halogen atoms; and acid addition salts thereof.
4. A compound according to claim 1 wherein R1 is a halo-substituted pyridyl group.
£ ' -*
5. A compound according to claim 1 wherein R2 is a hydrogen or haloalkyl, haloalkenyl or haloaralkyl group.
6. A compound according to claim 4 wherein R2 is a haloalkyl or haloalkenyl group.
7. A compound according to claim 6 wherein R2 is a fluoroalkyl or fluoroalkenyl group.
20
8. A compound according to claim 4 where R1 is a 5-halopyrid-3-yl group.
)
9. A compound according to claim 8 wherein R2 is fluoroethyl, difluoroethvl or trifluoroethyl.
25
10. An insecticidal acaricidal or nematicidal composition comprising an insecticidally, acaricidally or nematicidally effective amount of a compound according to claim 1 and a ^suitable carrier or diluent.
11. A method of combating and controlling insect, acerine or nematode pests at a locus which comprises treating the pests or the locus of the pests with an effective amount of a composition according to claim 10.
12. A method according to claim 11 wherein the pests are insect pests of growing plants.
AP/P/97/0 1 1 39
13. A method of preparing a compound of formula (I) where R2 is not hydrogen which comprises reacting a compound of formula (H):
/ (II)
F. CN with a compound of formula R“L where L is a leaving group in the presence of a base.
14. A process according to claim 13 wherein L represents halide or triflate.
15. A process of preparing a compound of formula (I) which comprises reacting a compound of formula (VI):
/N\ (VI) \y
CN with a compound of formula R’Hal where Hal is a halide in the presence of a base.
16. A process of preparing a compound of formula (VI):
R2 (VI
AP-00803
- 75 which comprises reacting a compound of formula (VII):
H
CN with a compound of formula R2L where L is a leaving group in the presence of a base. 5
17. A compound of formula (VI):
(VI)
CN wherein R2 represents hydrogen or cyano or a group selected from alkyl, aryl, hetroaryl, aralkyl, hetroarylalkyl, alkenyl, aralkenyl, alkynyl, alkoxycarbonyl, alkanesulfonyl, arenesulfonyl, alkanyloxycarbonyl, aralkyloxycarbonyl, aryloxycarbonyl, hertocyclylalkyl, carbamyl or dithiocarboxyl groups, said groups comprising from 1 to 15 carbon atoms, said groups being optionally substituted with one or more substituents selected from, halogen, cyano, carboxyl, carboxylic acyl, arbamyl, alkoxycarbonyl, alkoxy, alkylenedioxy, hydroxy, nitro, haloalkyl, alkyl, amino, acyclamino, imidate and phosphonato groups; and acid addition salts, quaternary ammonium salts and N-oxides derived therefrom; with the proviso that R2 is not methyl, 3-methylbutyl, n-hexyl, cyclohexylmethyl, benzyl, 4-chlorobenzyl, 4-methyIbenzyl, 4-methoxybenzyl, 3,4-dichlorobenzyl, 3-trifluromethylbenzyl, 2-phenethyl, 2-thienyl or trichloroethyl.
AP/P/9 7 /0 1 1 39
- 76 18. A compound of formula (VIII);
R2 (VIII) wherein R2 is 2-fluoroethyl, 2,2-difluoroethyl or 2,2,2-trifluoroethyl.
APAP/P/1997/001139A 1995-05-24 1996-05-13 Bicyclic amines. AP803A (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GBGB9510459.2A GB9510459D0 (en) 1995-05-24 1995-05-24 Bicyclic amines
PCT/GB1996/001151 WO1996037494A1 (en) 1995-05-24 1996-05-13 Bicyclic amines as insecticides

Publications (1)

Publication Number Publication Date
AP803A true AP803A (en) 2000-01-24

Family

ID=10774926

Family Applications (1)

Application Number Title Priority Date Filing Date
APAP/P/1997/001139A AP803A (en) 1995-05-24 1996-05-13 Bicyclic amines.

Country Status (35)

Country Link
US (4) US5922732A (en)
EP (1) EP0828739B1 (en)
JP (1) JP4276699B2 (en)
KR (1) KR100386035B1 (en)
CN (1) CN1066730C (en)
AP (1) AP803A (en)
AR (1) AR003419A1 (en)
AT (1) ATE223913T1 (en)
AU (1) AU710540B2 (en)
BG (1) BG102066A (en)
BR (1) BR9609112A (en)
CA (1) CA2217064A1 (en)
CZ (1) CZ368797A3 (en)
DE (1) DE69623614T2 (en)
DZ (1) DZ2037A1 (en)
EA (1) EA000468B1 (en)
ES (1) ES2183950T3 (en)
GB (2) GB9510459D0 (en)
HU (1) HU226985B1 (en)
ID (1) ID25629A (en)
IL (1) IL118254A (en)
MA (1) MA23880A1 (en)
MX (1) MX9708899A (en)
NZ (1) NZ307596A (en)
OA (1) OA10537A (en)
PL (1) PL323453A1 (en)
PT (1) PT828739E (en)
SI (1) SI9620088A (en)
SK (1) SK157897A3 (en)
TN (1) TNSN96078A1 (en)
TR (1) TR199701427T1 (en)
TW (1) TW334435B (en)
UY (1) UY24239A1 (en)
WO (1) WO1996037494A1 (en)
ZA (1) ZA963875B (en)

Families Citing this family (119)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB9510459D0 (en) 1995-05-24 1995-07-19 Zeneca Ltd Bicyclic amines
ES2218676T3 (en) * 1996-05-13 2004-11-16 Syngenta Limited BICYCLE AMINAS AS INSECTICIDES.
GB9623944D0 (en) * 1996-11-15 1997-01-08 Zeneca Ltd Bicyclic amine derivatives
GB9624114D0 (en) * 1996-11-20 1997-01-08 Zeneca Ltd Pesticidal bicyclic amine derivatives
GB9624501D0 (en) * 1996-11-26 1997-01-15 Zeneca Ltd Insecticial compositions and method
GB9624611D0 (en) * 1996-11-26 1997-01-15 Zeneca Ltd Bicyclic amine compounds
EP0944627B1 (en) * 1996-11-26 2004-02-18 Syngenta Limited 8-azabicyclo 3.2.1]octane-, 8-azabicyclo 3.2.1]oct-6-ene-, 9-azabicyclo 3.3.1]nonane-, 9-aza-3-oxabicyclo 3.3.1]nonane- and 9-aza-3-thiabicyclo 3.3.1]nonane derivatives, their preparation and their use as insecticides
GB9706574D0 (en) * 1997-04-01 1997-05-21 Zeneca Ltd Cyano substituted cycloalkanes
GB9724693D0 (en) 1997-11-21 1998-01-21 Zeneca Ltd Chemical compounds
GB9726033D0 (en) 1997-12-09 1998-02-04 Zeneca Ltd Chemical process
TWI221842B (en) 1997-12-11 2004-10-11 Syngenta Ltd Process for the preparation of 8-azabicyclo(3.2.1)octane derivatives
GB9809161D0 (en) * 1998-04-29 1998-07-01 Zeneca Ltd Chemical compounds
GB9913455D0 (en) 1999-06-09 1999-08-11 Zeneca Ltd Chemical process
CA2354606C (en) * 2000-08-03 2005-12-06 Pfizer Products Inc. Azabicycloalkane derivatives and therapeutic uses thereof
WO2002057263A1 (en) * 2001-01-17 2002-07-25 Syngenta Limited 8-azabicyclo "3.2.1.! octanes as insecticides
AU2002219383A1 (en) * 2001-01-17 2002-07-30 Syngenta Limited Bicyclic amines as insecticides
GB0101226D0 (en) * 2001-01-17 2001-02-28 Syngenta Ltd Chemical compounds
GB0117032D0 (en) * 2001-07-12 2001-09-05 Syngenta Ltd Chemical compounds
DE10152005A1 (en) * 2001-10-22 2003-04-30 Bayer Cropscience Ag Pyrazolyl substituted heterocycles
DE10160007A1 (en) 2001-12-06 2003-06-18 Bayer Cropscience Ag [1.2] oxazine-3,5-dione
DE10218231A1 (en) 2002-04-24 2003-11-06 Bayer Cropscience Ag methylthiophenecarboxanilides
DE10219035A1 (en) 2002-04-29 2003-11-13 Bayer Cropscience Ag biphenylcarboxamides
JP2004018506A (en) * 2002-06-20 2004-01-22 Bayer Ag Insecticidal phthalamide derivative
DE10238725A1 (en) * 2002-08-23 2004-03-04 Bayer Cropscience Ag New heterocyclyl-substituted 2-(difluorobutenyl-sulfanyl)-pyrimidine derivatives, useful as pesticides, e.g. insecticides, acaricides, nematocides, ectoparasiticides or antifouling agents
DE10246959A1 (en) * 2002-10-09 2004-04-22 Bayer Cropscience Ag New N-biphenyl thiazole-5-carboxamide derivatives, useful as antimicrobials for the protection of plants and technical materials, e.g. wood, against bacteria, fungi and algae
JP4043339B2 (en) * 2002-10-22 2008-02-06 川崎マイクロエレクトロニクス株式会社 Test method and test apparatus
DE10249055A1 (en) * 2002-10-22 2004-05-06 Bayer Cropscience Ag 2-Phenyl-2-substituted-1,3-diketones
DE10257080A1 (en) * 2002-12-06 2004-06-24 Bayer Cropscience Ag New pyrazoline carboxanilide derivatives, useful as pesticides, especially insecticides, for protecting plants, animals and materials
DE10258314A1 (en) * 2002-12-13 2004-06-24 Bayer Cropscience Ag New alkoxyimino-substituted biphenylcarboxamide derivatives, useful as pesticides, antimicrobials, herbicides and antimycotics, also their new intermediates
DE10301519A1 (en) * 2003-01-17 2004-07-29 Bayer Cropscience Ag New substituted 9-keto-spinosyn derivatives, useful for control of animal pests and microorganisms, in plant protection and veterinary medicine, also new intermediates
DE10303589A1 (en) * 2003-01-29 2004-08-12 Bayer Cropscience Ag pyrazolylcarboxanilides
CA2515922A1 (en) 2003-02-14 2004-08-26 Ralf Dunkel Oxathiin carboxamide
DE10311300A1 (en) 2003-03-14 2004-09-23 Bayer Cropscience Ag New 2-alkoxy-4-halo-6-alkylphenyl-substituted (hetero)cyclic ketoenols, useful as total or selective herbicides and pesticides, e.g. insecticides, acaricides and nematocides for plant protection
JP4648324B2 (en) * 2003-05-21 2011-03-09 バイエル・クロツプサイエンス・アクチエンゲゼルシヤフト Iodopyrazolyl carboxyanilides
DE10326386A1 (en) * 2003-06-12 2004-12-30 Bayer Cropscience Ag N-heterocyclyl-phenyl-substituted cyclic ketoenols
CN1845673A (en) * 2003-07-10 2006-10-11 拜尔农作物科学股份公司 Pyridinylanilides
DE10331675A1 (en) 2003-07-14 2005-02-10 Bayer Cropscience Ag Hetaryl-substituted pyrazolidinedione derivatives
DE10337497A1 (en) 2003-08-14 2005-03-10 Bayer Cropscience Ag 4-biphenyl-pyrazolidine-3,5-dione derivatives
DE10337496A1 (en) 2003-08-14 2005-04-14 Bayer Cropscience Ag 4-biphenyl-4-substituted-pyrazolidine-3,5-dione
DE10343872A1 (en) * 2003-09-23 2005-04-21 Bayer Cropscience Ag Agrochemical suspension concentrates containing azole and/or strobilurin, e.g. the fungicide tebuconazole, containing alkanol ethoxylate penetration promoter and specific polymeric dispersant to increase activity
DE10349502A1 (en) * 2003-10-23 2005-05-25 Bayer Cropscience Ag 1.3 Dimethylbutylcarboxanilide
MXPA06004308A (en) 2003-10-23 2006-06-05 Bayer Cropscience Ag Isopentyl carboxanilides for combating undesired micro-organisms.
DE10349497A1 (en) * 2003-10-23 2005-05-25 Bayer Cropscience Ag N-substituted pyrazolylcarboxanilides
IN2004DE01799A (en) * 2003-10-23 2007-01-12 Bayer Cropscience Ag
DE10354607A1 (en) 2003-11-21 2005-06-16 Bayer Cropscience Ag Siylated carboxamides
DE10357568A1 (en) * 2003-12-10 2005-07-07 Bayer Cropscience Ag pyrazolopyrimidine
DE102004003493A1 (en) * 2004-01-23 2005-08-11 Bayer Cropscience Ag 5-Phenylpyrimidines
DE102004005786A1 (en) 2004-02-06 2005-08-25 Bayer Cropscience Ag Haloalkylcarboxamide
DE102004005785A1 (en) 2004-02-06 2005-08-25 Bayer Cropscience Ag 2-Halogenfuryl / thienyl-3-carboxamide
DE102004006324A1 (en) * 2004-02-10 2005-08-25 Bayer Cropscience Ag Mixtures useful for controlling animal pests, comprising thiacloprid and pyrethroid
DE102004007076A1 (en) * 2004-02-13 2005-08-25 Bayer Cropscience Ag New imidazolopyrimidine derivatives useful for controlling unwanted microorganisms, e.g. phytopathogenic fungi
DE102004008807A1 (en) * 2004-02-20 2005-09-08 Bayer Cropscience Ag pyrazolopyrimidine
JP2006076990A (en) 2004-03-12 2006-03-23 Bayer Cropscience Ag Insecticidal benzenedicarboxamide compounds
DE102004012901A1 (en) 2004-03-17 2005-10-06 Bayer Cropscience Ag Silylated carboxamides
DE102004014620A1 (en) 2004-03-25 2005-10-06 Bayer Cropscience Ag 2,4,6-phenyl-substituted cyclic ketoenols
WO2005095380A1 (en) 2004-03-31 2005-10-13 Nippon Soda Co., Ltd. Cyclic amine compound and pest control agent
DE102004032418A1 (en) * 2004-04-07 2005-10-27 Bayer Cropscience Ag Drug combinations with insecticidal properties
DE102004020840A1 (en) 2004-04-27 2005-11-24 Bayer Cropscience Ag Use of Alkylcarboxamides as Penetration Promoters
DE102004022897A1 (en) * 2004-05-10 2005-12-08 Bayer Cropscience Ag Azinyl-imidazoazines
DE102004030753A1 (en) 2004-06-25 2006-01-19 Bayer Cropscience Ag 3'-alkoxy spirocyclic tetramic and tri-acids
DE102004041530A1 (en) 2004-08-27 2006-03-02 Bayer Cropscience Ag biphenyl thiazole carboxamides
DE102004059725A1 (en) 2004-12-11 2006-06-22 Bayer Cropscience Ag 2-alkyl-cycloalk (en) yl-carboxamide
DE102004062513A1 (en) 2004-12-24 2006-07-06 Bayer Cropscience Ag Insecticides based on neonicotinoids and selected strobilurins
DE102004062512A1 (en) 2004-12-24 2006-07-06 Bayer Cropscience Ag Synergistic mixtures with insecticidal and fungicidal action
US20060173037A1 (en) * 2005-01-10 2006-08-03 Nathalie Schlienger Aminophenyl derivatives as selective androgen receptor modulators
CA2594340C (en) 2005-01-10 2015-11-10 Acadia Pharmaceuticals Inc. Aminophenyl derivatives as selective androgen receptor modulators
DE102005008021A1 (en) 2005-02-22 2006-08-24 Bayer Cropscience Ag New spiroketal-substituted cyclic ketoenol compounds used for combating animal parasites, undesired plant growth and/or undesired microorganisms
DE102005022147A1 (en) 2005-04-28 2006-11-02 Bayer Cropscience Ag Active agent combination, useful to e.g. combat animal parasites and phytopathogenic fungus, comprises a carboxyamide compound and/or at least an active agent e.g. acetylcholine-receptor-agonist/antagonist
JP2009504773A (en) * 2005-08-19 2009-02-05 エラン ファーマシューティカルズ，インコーポレイテッド Bridged N-bicyclic sulfonamide inhibitors of gamma secretase
US8338607B2 (en) 2005-10-06 2012-12-25 Nippon Soda Co., Ltd. Cyclic amine compounds and agents for pest control
DE102005057837A1 (en) 2005-12-03 2007-06-06 Bayer Cropscience Ag Fungicidal combination of active ingredients
DE102005058838A1 (en) 2005-12-09 2007-06-14 Bayer Cropscience Ag Fungicidal combination of active ingredients
DE102005060464A1 (en) * 2005-12-17 2007-06-28 Bayer Cropscience Ag Pyrazolylcarboxamide
DE102005060467A1 (en) 2005-12-17 2007-06-21 Bayer Cropscience Ag carboxamides
DE102005060466A1 (en) 2005-12-17 2007-06-28 Bayer Cropscience Ag carboxamides
DE102005060462A1 (en) 2005-12-17 2007-06-28 Bayer Cropscience Ag biphenylcarboxamides
DE102006056544A1 (en) 2006-11-29 2008-06-05 Bayer Cropscience Ag Insecticidal active substance combinations (formononetin + insecticides)
DE102006058623A1 (en) * 2006-12-08 2008-06-12 Bayer Cropscience Ag Oxooxetane as a fungicidal agent
CL2007003744A1 (en) 2006-12-22 2008-07-11 Bayer Cropscience Ag COMPOSITION THAT INCLUDES A 2-PYRIDILMETILBENZAMIDE DERIVATIVE AND AN INSECTICIDE COMPOUND; AND METHOD TO CONTROL FITOPATOGENOS CULTURES AND INSECTS FACING OR PREVENTIVELY.
CL2007003743A1 (en) 2006-12-22 2008-07-11 Bayer Cropscience Ag COMPOSITION THAT INCLUDES FENAMIDONA AND AN INSECTICIDE COMPOUND; AND METHOD TO CONTROL FITOPATOGENOS CULTURES AND INSECTS FACING OR PREVENTIVELY.
PL2124557T3 (en) * 2007-02-02 2015-06-30 Plant Health Care Inc Synergistic fungicidal combinations comprising formononetin
DE102007010801A1 (en) 2007-03-02 2008-09-04 Bayer Cropscience Ag Use of new and known 2,4-diaminopyrimidine derivatives as fungicides, especially for controlling phytopathogenic fungi
TW200904331A (en) 2007-06-15 2009-02-01 Bayer Cropscience Sa Pesticidal composition comprising a strigolactone derivative and an insecticide compound
GB0713602D0 (en) * 2007-07-12 2007-08-22 Syngenta Participations Ag Chemical compounds
EP2183228B1 (en) 2007-07-26 2014-08-20 Vitae Pharmaceuticals, Inc. CYCLIC INHIBITORS OF 11ß -HYDROXYSTERIOD DEHYDROGENASE 1
AR069207A1 (en) 2007-11-07 2010-01-06 Vitae Pharmaceuticals Inc CYCLIC UREAS AS INHIBITORS OF THE 11 BETA - HIDROXI-ESTEROIDE DESHIDROGENASA 1
WO2009063061A2 (en) 2007-11-16 2009-05-22 Boehringer Ingelheim International Gmbh Aryl- and heteroarylcarbonyl derivatives of benzomorphanes and related scaffolds, medicaments containing such compounds and their use
CA2708303A1 (en) 2007-12-11 2009-06-18 Vitae Pharmaceuticals, Inc. Cyclic urea inhibitors of 11.beta.-hydroxysteroid dehydrogenase 1
TW200934490A (en) 2008-01-07 2009-08-16 Vitae Pharmaceuticals Inc Lactam inhibitors of 11 &abgr;-hydroxysteroid dehydrogenase 1
CA2712500A1 (en) 2008-01-24 2009-07-30 Vitae Pharmaceuticals, Inc. Cyclic carbazate and semicarbazide inhibitors of 11beta-hydroxysteroid dehydrogenase 1
EP2254872A2 (en) 2008-02-15 2010-12-01 Vitae Pharmaceuticals, Inc. Cycloalkyl lactame derivatives as inhibitors of 11-beta-hydroxysteroid dehydrogenase 1
CA2722427A1 (en) 2008-05-01 2009-11-05 Vitae Pharmaceuticals, Inc. Cyclic inhibitors of 11beta-hydroxysteroid dehydrogenase 1
CA2723039A1 (en) 2008-05-01 2009-11-05 Vitae Pharmaceuticals, Inc. Cyclic inhibitors of 11beta-hydroxysteroid dehydrogenase 1
EP2291370B1 (en) 2008-05-01 2013-11-27 Vitae Pharmaceuticals, Inc. Cyclic inhibitors of 11beta-hydroxysteroid dehydrogenase 1
TW200950780A (en) 2008-05-13 2009-12-16 Boehringer Ingelheim Int Alicyclic carboxylic acid derivatives of benzomorphans and related scaffolds, medicaments containing such compounds and their use
EP2145538A1 (en) 2008-07-15 2010-01-20 Georg-August-Universität Göttingen Stiftung Öffentlichen Rechts Plant and material preservative
AU2009274567B2 (en) 2008-07-25 2013-04-04 Boehringer Ingelheim International Gmbh Cyclic inhibitors of 11 beta-hydroxysteroid dehydrogenase 1
WO2010010157A2 (en) 2008-07-25 2010-01-28 Boehringer Ingelheim International Gmbh INHIBITORS OF 11beta-HYDROXYSTEROID DEHYDROGENASE 1
CA2744946A1 (en) 2009-02-04 2010-08-12 Boehringer Ingelheim International Gmbh Cyclic inhibitors of 11.beta.-hydroxysteroid dehydrogenase 1
US8680093B2 (en) 2009-04-30 2014-03-25 Vitae Pharmaceuticals, Inc. Cyclic inhibitors of 11beta-hydroxysteroid dehydrogenase 1
WO2011011123A1 (en) 2009-06-11 2011-01-27 Vitae Pharmaceuticals, Inc. Cyclic inhibitors of 11beta-hydroxysteroid dehydrogenase 1 based on the 1,3 -oxazinan- 2 -one structure
AR078887A1 (en) 2009-11-06 2011-12-07 Boehringer Ingelheim Int ARILO AND HETEROARILCARBONILO DERIVATIVES OF HEXAHYDROINDENOPIRIDINE AND OCTAHYDROBENZOQUINOLINE AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM.
US8933072B2 (en) 2010-06-16 2015-01-13 Vitae Pharmaceuticals, Inc. Substituted 5-,6- and 7-membered heterocycles, medicaments containing such compounds, and their use
JP5813106B2 (en) 2010-06-25 2015-11-17 ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング Azaspirohexanone as an inhibitor of 11-β-HSD1 for the treatment of metabolic disorders
EP2635268A1 (en) 2010-11-02 2013-09-11 Boehringer Ingelheim International GmbH Pharmaceutical combinations for the treatment of metabolic disorders
TWI537258B (en) 2010-11-05 2016-06-11 百靈佳殷格翰國際股份有限公司 Aryl-and heteroarylcarbonyl derivatives of hexahydroindenopyridine and octahydrobenzoquinoline
CA2823999C (en) 2011-03-10 2020-03-24 Bayer Intellectual Property Gmbh Use of lipochito-oligosaccharide compounds for safeguarding seed safety of treated seeds
US8735585B2 (en) 2011-08-17 2014-05-27 Boehringer Ingelheim International Gmbh Indenopyridine derivatives
EP2978317A1 (en) * 2013-03-28 2016-02-03 Syngenta Participations AG Methods of controlling neonicotinoid resistant pests
US20160050930A1 (en) * 2013-03-28 2016-02-25 Syngenta Limited Methods of controlling neonicotinoid resistant pests
EP2978318A1 (en) * 2013-03-28 2016-02-03 Syngenta Participations AG Methods of controlling neonicotinoid resistant pests
BR112016004352A2 (en) * 2013-09-06 2017-09-12 Syngenta Participations Ag insecticide compounds
BR122023020910A2 (en) 2014-09-17 2024-01-30 Spogen Biotech Inc METHOD FOR SUPPLYING PROTEINS OR PEPTIDES TO AN ANIMAL
WO2016050567A1 (en) * 2014-10-01 2016-04-07 Syngenta Participations Ag Insecticidal cyanotropane derivatives
EP3386304A1 (en) 2015-12-07 2018-10-17 Valent BioSciences LLC Concentrated gibberellin solution formulations
MX2020012570A (en) 2018-05-25 2021-01-29 Bayer Ag Agrochemical formulations containing a polymeric crystal growth inhibitor.
EP3649858A1 (en) 2018-11-06 2020-05-13 Bayer AG Agrochemical formulations containing a polymeric crystal growth inhibitor
CN111406741B (en) * 2020-01-16 2021-11-02 陶俊德 Application of acetonitrile as soil fumigation chemical agent and application method thereof
WO2024069628A1 (en) 2022-09-29 2024-04-04 Adama Makhteshim Ltd. Concentrated agrochemical compositions of anthranilic diamides

Family Cites Families (33)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3120537A (en) * 1958-04-30 1964-02-04 Sterling Drug Inc 3-(monocarbocyclic aryl)-3-carboxytropanes and esters thereof
US3133073A (en) * 1959-12-10 1964-05-12 Sterling Drug Inc 3-aryl-1, 5-iminocycloalkanes and preparation thereof
US3308131A (en) * 1962-12-06 1967-03-07 Du Pont Tertiary carbamyl triazoles
NL129205C (en) * 1963-02-25
NL6605944A (en) * 1965-05-04 1966-11-07
US3501461A (en) * 1968-01-18 1970-03-17 Allied Chem Azabicyclic phosphonate
US3546232A (en) * 1968-10-25 1970-12-08 Smithkline Corp 3 - phenyl - 8 - thianaphthenylalkyl derivatives of nortropine and nortropidine
US3657257A (en) * 1970-08-31 1972-04-18 Robins Co Inc A H 3-aryl-8-carbamoyl nortropanes
LU76173A1 (en) * 1976-11-11 1978-07-10
US4180669A (en) * 1976-12-13 1979-12-25 Abbott Laboratories 2-(N-phenethyl-4-piperidino)-5-pentyl resorcinol
US4350691A (en) * 1979-12-20 1982-09-21 Beecham Group Limited Certain azabicyclocarboxamides and compositions containing same
DE3045688A1 (en) * 1980-12-04 1982-07-08 C.H. Boehringer Sohn, 6507 Ingelheim NEW 8-ARYLALKYL-3-PHENYL-3-NORTROPANOLE, THE ACID ADDITION SALTS THEREOF, THE MEDICINAL PRODUCTS CONTAINING THE SAME AND METHOD FOR THE PRODUCTION THEREOF
CA1244028A (en) * 1983-04-14 1988-11-01 Hans Maag Pyrimidine derivatives
FR2548666A1 (en) * 1983-07-08 1985-01-11 Delalande Sa New nortropane and granatane derivatives, process for their preparation and their application in therapeutics
EP0216625A3 (en) * 1985-09-24 1988-08-17 The Wellcome Foundation Limited Pesticidal compounds
NZ225999A (en) * 1987-09-10 1992-04-28 Merck Sharp & Dohme Azacyclic- or azabicyclic-substituted thiadiazole derivatives and pharmaceutical compositions
DE3852463T2 (en) * 1987-10-13 1995-05-18 United States Surgical Corp Trocar cutlery.
DE3850742T2 (en) * 1987-11-04 1994-10-27 Beecham Group Plc New 4-oxobenzotriazines and 4-oxoquinazolines.
EP0398578B1 (en) * 1989-05-17 1997-03-12 Pfizer Inc. 2-piperidino-1-alkanol derivatives as antiischemic agents
ATE192149T1 (en) * 1990-05-10 2000-05-15 Pfizer NEUROPROTECTIVE INDOLONES AND RELATED DERIVATIVES
EP0540526B1 (en) * 1990-07-23 1994-12-28 Pfizer Inc. Quinuclidine derivatives
FI111367B (en) * 1991-02-04 2003-07-15 Aventis Pharma Inc Process for the preparation of therapeutically useful N- (aryloxyalkyl) heteroaryl-8-azabicyclo [3.2.1] octane derivatives and intermediates used in the process
US5491148A (en) * 1991-04-26 1996-02-13 Syntex (U.S.A.) Inc. Isoquinolinone and dihydroisoquinolinone 5-HT3 receptor antagonists
NZ243065A (en) * 1991-06-13 1995-07-26 Lundbeck & Co As H Piperidine derivatives and pharmaceutical compositions
JPH06509069A (en) * 1991-06-27 1994-10-13 バージニア・コモンウェルス・ユニバーシティ Sigma receptor ligands and their uses
US5244906A (en) * 1992-01-23 1993-09-14 Dowelanco Insect control with substituted oxadiazole and thiadiazole compounds
DK78692D0 (en) * 1992-06-12 1992-06-12 Lundbeck & Co As H DIMER PIPERIDINE AND PIPERAZINE DERIVATIVES
WO1995003306A1 (en) * 1993-07-22 1995-02-02 E.I. Du Pont De Nemours And Company Arthropodicidal azacyclic heterocycles
US5393767A (en) * 1993-08-26 1995-02-28 Dowelanco Insect control with substituted triazole and tetrazole compounds
WO1996036637A1 (en) * 1995-05-17 1996-11-21 R.J. Reynolds Tobacco Company Pharmaceutical compositions for prevention and treatment of central nervous system disorders
GB9510459D0 (en) * 1995-05-24 1995-07-19 Zeneca Ltd Bicyclic amines
TR199800628T2 (en) * 1995-10-13 1998-07-21 Neurosearch A/S 8-Azabisiklo $ 3.2.1] oct-2-en t�revleri, büllar�n haz�rlanmas� ve kullan�m�.
ES2218676T3 (en) * 1996-05-13 2004-11-16 Syngenta Limited BICYCLE AMINAS AS INSECTICIDES.

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
J. OF MEDICINAL CHEMISTRY V.18 NO. 5, 1975, WASHINGTON US, pages 496-501 *

Also Published As

Publication number Publication date
IL118254A0 (en) 1996-09-12
PL323453A1 (en) 1998-03-30
AU710540B2 (en) 1999-09-23
IL118254A (en) 2002-04-21
TW334435B (en) 1998-06-21
AR003419A1 (en) 1998-08-05
ATE223913T1 (en) 2002-09-15
DE69623614T2 (en) 2003-01-30
MX9708899A (en) 1998-03-31
BR9609112A (en) 1999-02-02
SI9620088A (en) 1998-06-30
GB9609978D0 (en) 1996-07-17
US6207676B1 (en) 2001-03-27
JP4276699B2 (en) 2009-06-10
KR100386035B1 (en) 2003-09-22
MA23880A1 (en) 1996-12-31
ES2183950T3 (en) 2003-04-01
EP0828739B1 (en) 2002-09-11
OA10537A (en) 2002-04-25
CN1185154A (en) 1998-06-17
PT828739E (en) 2002-12-31
HUP9802708A3 (en) 1999-03-29
UY24239A1 (en) 1996-06-07
SK157897A3 (en) 1998-05-06
JPH11505826A (en) 1999-05-25
ZA963875B (en) 1996-12-02
GB9510459D0 (en) 1995-07-19
US6391883B1 (en) 2002-05-21
US6573275B1 (en) 2003-06-03
BG102066A (en) 1998-09-30
HU226985B1 (en) 2010-04-28
CN1066730C (en) 2001-06-06
CA2217064A1 (en) 1996-11-28
TNSN96078A1 (en) 2005-03-15
DZ2037A1 (en) 2002-10-23
NZ307596A (en) 1999-05-28
EP0828739A1 (en) 1998-03-18
WO1996037494A1 (en) 1996-11-28
DE69623614D1 (en) 2002-10-17
TR199701427T1 (en) 1998-04-21
ID25629A (en) 1999-05-23
HUP9802708A2 (en) 1999-02-01
AU5698896A (en) 1996-12-11
US5922732A (en) 1999-07-13
CZ368797A3 (en) 1998-02-18
EA000468B1 (en) 1999-08-26
GB2301819A (en) 1996-12-18
EA199700416A1 (en) 1998-10-29
GB2301819B (en) 1999-05-19
KR19990021936A (en) 1999-03-25

Similar Documents

Publication Publication Date Title
AP803A (en) Bicyclic amines.
US6174894B1 (en) Bicyclic amine derivatives
US6291474B1 (en) Bicyclic amine derivatives
US6066646A (en) Bicyclic amine derivatives
US5859024A (en) Insecticidal, acaricidal or nematicidal 3-cyano-8-azabicyclo 3.2.1!octane derivatives
US6294545B1 (en) Bicyclic amines and their use as insecticides
AU720176B2 (en) Bicyclic amines as insecticides
EP0942909B1 (en) Bicyclic amine derivatives
GB2324795A (en) Bicyclic Amines
GB2319524A (en) Nortropane derivatives for use as insecticides