WO1995029155A1 - Novel antitumour compounds with antimitotic activity - Google Patents

Novel antitumour compounds with antimitotic activity Download PDF

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Publication number
WO1995029155A1
WO1995029155A1 PCT/SE1995/000393 SE9500393W WO9529155A1 WO 1995029155 A1 WO1995029155 A1 WO 1995029155A1 SE 9500393 W SE9500393 W SE 9500393W WO 9529155 A1 WO9529155 A1 WO 9529155A1
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Prior art keywords
benzyl
biphenyl
yloxy
methyl
ethyl
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PCT/SE1995/000393
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French (fr)
Inventor
Tomas Fex
Anders Stamvik
Jan-Inge Carlsson
Beryl Asp
Anita BILLSTRÖM
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Pharmacia Ab
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Priority to AU23545/95A priority Critical patent/AU2354595A/en
Publication of WO1995029155A1 publication Critical patent/WO1995029155A1/en

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Abstract

Novel N-acyl-aminoalkyl phenyl ether compounds having general formula (I), wherein A is an aromatic ring such as phenyl, thienyl, furyl, pyridyl; R1, R2 and R3 are selected from H, alkyl, halogen, electron acceptors and electron donors; m is 0, 1 or 2; R4 is H or lower alkyl; R5 is NR6R7, OR8 or lower alkyl or lower cycloalkyl; R6 and R7 are H or lower alkyl or lower cycloalkyl; R8 is lower alkyl or lower cycloalkyl; Y is O or S; n is 2 or 3; R9 is H or lower alkyl; X is O or CH2; R10, R11 and R12 are selected from H, 'alkyl', halogen, electron acceptors and electron donors or one of them may be (a), wherein Z is a bond, O, CO or CH2; and wherein B is an aromatic ring such as phenyl or pyridyl and R13, R14 and R15 are selected from H, 'alkyl', halogen, electron acceptors and electron donors, and pharmaceutically acceptable salts thereof. The invention also comprises pharmaceuticals, especially anticancer and/or antimitotic drugs, comprising one or more of the above-mentioned compounds.

Description

NOVEL ANTITUMOUR COMPOUNDS WITH ANTIMITOTIC ACTIVITY
This invention relates to novel N-acyl-aminoalkyl phenyl ether compounds having antitumour and antimitotic effetcs. Background Antitumour compounds with antimitotic activity have wide-spread use for the treatment of different forms of cancer. The vinca alkaloids, vincristine and vinblastine, are natural products isolated from Vinca rosea and owe their antitumour properties to an inhibition of microtubule formation, a cellular component which is an important part of the cytoskeleton. Microtubules are especially important during mitosis, and inhibition of their function causes inhibition of the cell cycle at this stage. As is the case with many types of cancer treatment the clinical effects in using vinca alkaloids are not sufficient and they are often associated with serious side effects, among which neuro- toxicity is specific for this type of drugs.
Colchicine is another antitumour alkaloid which is a microtubule inhibitor. It is, however, rarely used in the clinic for tumour treatment, partly due to serious side effects.
Taxol is a new antitumour drug which also owes its activity to an interaction with microtubules. It causes "stabilisation", thereby disrupting normal microtubule func¬ tion. Lack of useful effects against some types of tumours and serious side effects cause limitations in its use.
Estramustine is an estradiol carbamate which is used in the treatment of prostatic cancer, and which has been found to inhibit microtubule function.
Chemotherapy of cancer is often unsuccessful and more effective anti¬ mitotic drugs are therefore of great interest.
Prior Art
No compounds structurally related to the active compounds of the present invention are known to have antitumour and antimitotic activity.
DE 3506814 (BASF AG) describes fungicidal compounds such as
Figure imgf000004_0001
AU 491880 (BOOTS CO. LTD) describes fungicidal compounds such as
Figure imgf000004_0002
EP 84236 (FBC LTD.) describes fungicidal compounds such as
Figure imgf000004_0003
All three types of compounds above are characterized by having a hetero¬ cyclic group in the acyl moiety, which is not found in the compounds of the present invention. In addition, they possess different biological activity.
GB 753,976 (CILAG LTD.) describes acaricidal compounds of the following structure
Figure imgf000005_0001
The compounds are not noted for antitumour activity, and the α,β unsatu¬ rated acyl moiety appears to be crucial for biologic activity.
Objects of the Invention
Estramustine has relatively low antitumour activity and is clinically asso¬ ciated with estrogenic side effects. We have, therefore, sought to find new compounds with higher activity and less or no estrogenic side effects. Accordingly, one object of the present invention is to provide new com¬ pounds having the general formula I having antitumour activity.
A second object of the invention is to provide compounds having antimitotic activity.
A third object of the invention is to provide processes for preparing the new compounds according to the first and second objects.
A fourth object is to provide prodrugs of the compounds of the present invention in cases where this is appropriate in order to improve for example pharma¬ ceutical and pharmacokinetic properties. A fifth object of the invention is to provide compositions containing as an active ingredient one or more of the compounds having the general formula I, prefe¬ rably together with a pharmaceutically acceptable carrier and, if desired, other pharmacologically active agents. A sixth object of the invention is to provide a method of treating cancer by adminstehng one or more compounds having the general formula I or their prodrugs.
Other objects of the invention will become apparent to one skilled in the art, and still other objects will become apparent hereinafter.
Summary of the Invention
The present invention relates to novel N-acyl-aminoalkyl phenyl ether compounds having the general formula I
Figure imgf000006_0001
wherein A is an aromatic ring such as phenyl, thienyl, furyl, pyridyl
R,, R2 and R3 are selected from H and the group of substituents shown in table 1 , m is 0, 1 or 2 R4 is H or lower alkyl
R5 is NR6R7, OR8, H or lower alkyl or lower cycloalkyl R6 and R7 are H or lower alkyl or lower cycloalkyl R8 is lower alkyl or lower cycloalkyl Y is O or S n is 2 or 3
R9 is H or lower alkyl X is O or S
R10, R„ and R12 are selected from H and the group of substituents shown in table 1 , or one of them may be
R .3
Z - B - R14
wherein Z is a bond, O, CO or CH_ and wherein
B is an aromatic ring such as phenyl or pyridyl and R13, R14 and R15 are selected from H and the group of substituents shown in table 1 , two of R10, R„ and R12 may together be groups such as -(CH2)4- and - (CH=CH)2-, or one of R10, R and R12 and one of R13, R14 and R1S may together be groups such as -CH2-, -CH2CH2-, -CH2CH2-CH2- and -CH=CH- and R10, R„ and R12 may also, together with the aromatic ring, be part of a steroid skeleton, with the provisio that Rs is saturated lower alkyl or saturated lower cyclo¬ alkyl when none of R10, R„ and R12 is R13
Z - B - R14
R.s As regards the substituents R13, R14 and R15 it has been found that they can be of very varied structure, some examples being included in the detailed description of the invention. Table 1 Examples of substituents grouped according to their properties (Ref. 7): "Alkyl": Me, Et, i-Pr, t-Bu, CH2Ph, Ph. Halogen: F, Cl, Br, I.
Electron acceptors: CF3, C02Me, COPh, CHO, COOH, S02NH2, S02Me, CN, N02.
Electron donors: OMe, OH, OPh, SMe, NH2, NMe2, NHAc.
When not stated otherwise lower alkyl is meant to include straight, branched saturated and unsaturated alkyl fragments having 1-6 carbon atoms and cykloalkyl is meant to include saturated and unsaturated cyclic alkyl fragments having 3-6 carbon atoms.
The following substituents are preferred:
R„ R2 and R3 = H or F
R4 = H or Me, especially H m = 1
Y = O
R5 = NR6R7 whereby one of R6 and R7 is H and the other is Me or Et, especially Me R9 = H n = 2
X = O
R10, R„ = H or F
R„ R12 = Z - B - R14 in p- or m-position ι
R .5
Z is a bond B = phenyl R13 and R14 = H or F R1S = H, OH or O-alkyl, especially OH.
The compounds of the present invention which contain salt-forming func¬ tional groups may also be in the form of salts with suitable organic and inorganic ions. In some instances it may be advantageous to prepare and use prodrugs of the compounds included in the present invention. Thus, prodrugs may be used to improve pharmaceutical and pharmacokinetic properties. Many different functional groups can be used for prodrug preparation and many different prodrugs can be used (Ref 8).
One example includes a phenolic hydroxyl group from which prodrugs such as esters, carbamates, phosphates, carbohydrate conjugates etc can be prepared.
Methods of Preparation
The compounds having the general formula I may be prepared by conven¬ tional methods.
Compounds of the general formula I wherein n = 2 and X is 0 or S may be prepared according to scheme 1. Scheme 1
Figure imgf000010_0001
Figure imgf000010_0002
(I)
Figure imgf000010_0003
Reducing agent
.
Figure imgf000010_0004
Figure imgf000010_0005
R5CYL3 or RsNCY (for R7=H)
Figure imgf000010_0006
Steps i) and ii) are alkylation reactions where L, and L2 are suitable leaving group such as halogen. Step iii) is an aminolysis reaction where M,0 is a suitable ester group such as methyl or ethyl ester. Step iv) is a reduction of the amide which can be accomplished by for example using diborane generated in situ from NaBH4 and BF3-etherate. Step v) is an acylation and R5CYL3 and R6NCY are common acylating agents wherein L3 is an appropriate leaving group, e. g. halogen. All other symbols have the meanings defined above.
Compounds of formula I can also be prepared as depicted in scheme 2. Scheme 2
Figure imgf000011_0001
Figure imgf000011_0002
The first step is an acylation wherein L4 and L5 are suitable leaving groups such as halogen, p-nitrophenoxy etc. In the subsequent step the leaving group is replaced by an appropriate amine. All symbols have the meanings defined above.
Another method to prepare the compounds of formula I is depicted in scheme 3. Scheme 3
Figure imgf000012_0001
Figure imgf000012_0002
R
Figure imgf000012_0003
. R5CYL3 or R^NCY (for R7=H)
Figure imgf000012_0004
The first step is an alkylation performed under basic reaction conditions. The second step is an alkylation of an amine. L6 and L7 are suitable leaving groups such as halogen or alkyl- or arylsulfonate. The subsequent acylation is the same as depicted in scheme 1. All other symbols have the meanings defined above.
As mentioned above the substituents R10, R„ and R12 may be of very varied structures. Consequently, a large number of synthetic reactions, well-known to the skilled organic chemist, can be used for their introduction and/or modification. Com¬ pounds of the present invention may thus serve as intermediates for the preparation of new, biologically active compounds which also lie within the scope of the invention. Several such examples are to be found in the detailed description of the invention. All symbols have the meanings defined above, and the B-substituent is in the meta- or para-position.
Detailed description of the invention
The following examples are intended to illustrate but not to limit the scope of the invention, although the compounds named are of particular interest for our intended purposes.
These compounds have been designated by numbers in the examples where their systematic names are given. These compounds are later referred to by a number code a:b, where a means the number of the example wherein the preparation of the compound in question is described, and b refers to the order of the compounds prepared according to that example. Thus, compound 1 :02 means the second compound prepared according to Example 1.
The structure of the compounds found in the examples are confirmed by NMR. Example 1.
This example illustrates the preparation of compounds of the general formula I above by reacting a secondary amine with an acylating agent, e.g an isocyanate.
Benzyl-[2-(biphenyl-4-yloxy)-ethyl]-amine (15:01) (34 g, 0.112 mol) is dissolved in methylene chloride (300 ml). Methyl isocyanate (10 g, 0.175 mol) is added. The resulting mixture is stirred for 2 hours at room temperature and eva¬ porated in vacuo.The product, 1-Benzyl-1-[2-(biphenyl-4-yloxy)-ethyl]-3-methyl-urea (1:01) is isolated, dried, and recrystallized from ethyl acetate (pure by TLC, mp 136°C). In essentially the same manner, the following compounds are obtained from the corresponding starting material: 1-Benzyl-1-[3-(biphenyl-4-yloxy)-propyl]-3-methyl-urea (1:02), mp 108°C from methyl isocyanate and Benzyl-[3-(biphenyl-4-yloxy)-propyl]-amine (16:01 )
1-[2-(Biphenyl-4-yloxy)-ethyl]-1-(4-methoxy-benzyl)-3-methyl-urea (1 :03), mp 124°C from methyl isocyanate and [2-(Biphenyl-4-yloxy)-ethyl]-(4-methoxy-benzyl)-amine (15:03)
1-[2-(Biphenyl-4-yloxy)-ethyl]-3-methyl-1-phenethyl-urea (1 :04), mp 92°C from methyl isocyanate and [2-(Biphenyl-4-yloxy)-ethyl]-phenethyl-amine (15:04)
1 -Benzyl-1 -[2-(biphenyl-4-yloxy)-ethyl]-3-cyclopropyl-urea (1 :05), mp 125°C from cyclopropyl isocyanate and benzyl-[2-(biphenyl-4-yloxy)-ethyl]-amine (15:01 )
1-[2-(Biphenyl-4-yloxy)-ethyl]-1-(2-bromo-benzyl)-3-methyl-urea (1:06), mp 142βC from methyl isocyanate and [2-(Biphenyl-4-yloxy)-ethyl]-(2-bromo-benzyl)-amine (15:06)
1-[2-(Biphenyl-4-yloxy)-ethyl]-3-methyl-1-pyridin-2-ylmethyl-urea, (1:07), mp 143°C from methyl isocyanate and [2-(Biphenyl-4-yloxy)-ethyl]-pyridin-2-ylmethyl-amine (15:07)
1-[2-(Biphenyl-4-yloxy)-ethyl]-3-methyl-1-(3-nitro-benzyl)-urea, (1:08), mp 124°C from methyl isocyanate and [2-(Biphenyl-4-yloxy)-ethyl]-(3-nitro-benzyl)-amine (15:08)
1 -[2-(Biphenyl-4-yloxy)-ethyl]-3-methyl-1 -(1 -phenyl-ethyl)-urea, (1 :10), mp 123°C from methyl isocyanate and
[2-(Biphenyl-4-yloxy)-ethyl]-(1-phenyl-ethyl)-amine (15:09)
1 -[2-(Biphenyl-4-yloxy)-ethyl]-3-methyl-1 -pyridin-3-ylmethyl-urea, (1 :11), mp 118°C from methyl isocyanate and
[2-(Biphenyl-4-yloxy)-ethyl]-pyridin-3-ylmethyl-amine (15:10)
1-Benzyl-1-(2-{4'-[2-(1-benzyl-3-methyl-ureido)-ethoxy]-biphenyl- 4-yloxy}-ethyl)-3-methyl-urea, (1 :12), mp 144βC from methyl isocyanate and
Benzyl-{2-[4'-(2-beπzylamino-ethoxy)-biphenyl-4-yloxy]-ethyl}- amine (15:11)
1-[2-(Biphenyl-4-yloxy)-ethyl]-1-furan-2-ylmethyl-3-methyl-urea, (1:13), mp 139βC from methyl isocyanate and [2-(Biphenyl-4-yloxy)-ethyl]-furan-2-ylmethyl-amine (15:12)
1-[2-(Biphenyl-4-yloxy)-ethyl]-3-methyl-1-thiophen-2-ylmethyl-urea, (1 :14), mp 148βC from methyl isocyanate and [2-(Biphenyl-4-yloxy)-ethyl]-thiophen-2-ylmethyl-amine (15:13)
1-Benzyl-1-[2-(4'-hydroxy-biphenyl-4-yloxy)-ethyl]-3-methyl-urea, (1 :15), mp 228βC from methyl isocyanate and 4'-(2-Benzylamino-ethoxy)-biphenyl-4-ol (15:14) 1-[2-(Biphenyl-4-yloxy)-ethyl]-1-(4-fluoro-benzyl)-3-methyl-urea, (1 :16), mp 110°C from methyl isocyanate and [2-(Biphenyl-4-yloxy)-ethyl]-(4-fluoro-benzyl)-amine (15:15)
1 -[2-(1 -biphenyl-4-yloxy)-ethyl)-1 -(2-fluoro-benzyl)-3-methyl-urea, (1 :17), mp 169βC from methyl isocyanate and [2-(Biphenyl-4-yloxy)-ethyl]-(2-fluoro-benzyl)-amine (15:16)
1-[2-(Biphenyl-4-yloxy)-ethyl]-1-(3-fluoro-benzyl)-3-methyl-urea, (1:18), mp 120βC from methyl isocyanate and [2-(Biphenyl-4-yloxy)-ethyl]-(3-fluoro-benzyl)-amine (15:17)
1-Benzyl-1-[2-(4'-methoxy-biphenyl-4-yloxy)-ethyl]-3-methyl-urea, (1:19), mp 149-151°C from methyl isocyanate and Benzyl-[2-(4'-methoxy-biphenyl-4-yloxy)-ethyl]-amine (15:18)
Carbamic acid, N-methyl 4'-[2-(1-benzyl-3-methyl-ureido)-ethoxy]- biphenyl-4-yl ester, (1:20), mp 106-108βC from methyl isocyanate and 4'-(2-Benzylamino-ethoxy)-biphenyl-4-ol (15:14)
1-Benzyl-1-[2-(biphenyl-4-yloxy)-ethyl]-3-propyl-urea, (1 :21), mp 99-100βC from n-propyl isocyanat and Benzyl-[2-(biphenyl-4-yloxy)-ethyl]-amine (15:01)
1-[2-(4'-Hydroxy-biphenyl-4-yloxy)-ethyl]-3-methyl- 1 -(4-methyl-benzyl)-urea, (1 :22), mp 201 °C from methyl isocyanate and
4'-[2-(4-Methyl-benzylamino)-ethoxy]-biphenyl-4-ol (15:19)
1-Benzyl-1-[2-(4'-hydroxy-biphenyl-4-yloxy)-ethyl]-3-propyl-urea, (1 :23), mp 167βC from n-propyl isocyanate and 4'-(2-Benzylamino-ethoxy)-biphenyl-4-ol (15:14)
1 -Benzyl-3-ethyl-1 -[2-(4'-hydroxy-biphenyl-4-yloxy)-ethyl]-urea, (1 :24), mp 158°C from ethyl isocyanate and 4'-(2-Benzylamino-ethoxy)-biphenyl-4-ol (15:19)
1 -(3-Fluoro-benzyl)-1 -[2-(4'-hydroxy-biphenyl-4-yloxy)-ethyl]-
3-methyl-urea, (1:25), mp 180βC from methyl isocyanate and 4'-[2-(3-Fluoro-benzylamino)-ethoxy]-biphenyl-4-ol (15:20)
1-Benzyl-1-[2-(4'-hydroxymethyl-biphenyl-4-yloxy)-ethyl]-3-methyl-urea, (1 :26), mp 110βC from methyl isocyanate and [4'-(2-Benzylamino-ethoxy)-biphenyl-4-yl]-methanol (15:21 )
1 -Benzyl-1 -{2-[4'-(1 -hydroxy-ethyl)-biphenyl-4-yloxy]-ethyl}- 3-methyl-urea, (1 :27), mp 105βC from methyl isocyanate and 1-[4'-(2-Benzylamino-ethoxy)-biphenyl-4-yl]-ethanol (15:22)
1-(3-Fluoro-benzyl)-1-[2-(4'-hydroxymethyl-biphenyl-4-yloxy)-ethyl]- 3-methyl-urea, (1 :28), mp 90-92°C from methyl isocyanate and
{4'-[2-(3-Fluoro-benzylamino)-ethoxy]-biphenyl-4-yl}-methanol (15:23)
1-(3,5-Difluoro-benzyl)-1-[2-(4'-hydroxy-biphenyl-4-yloxy)-ethyl]-
3-methyl-urea, (1 :29), mp 186°C from methyl isocyanate and
4'-[2-(3,5-Difluoro-benzylamino)-ethoxy]-biphenyl-4-ol (15:24)
1-[2-(3,3'-Difluoro-4'-{2-[1-(3-fluoro-benzyl)-3-methyl-ureido]- ethoxy}-biphenyl-4-yloxy)-ethyl]-1 -(3-fluoro-benzyl)-3-methyl-urea, (1 :30), mp 170°C from methyl isocyanate and (2-{3,3'-Difluoro-4'-[2-(3-fluoro-benzylamino)-ethoxy]-biphenyl-
4-yloxy}-ethyl)-(3-fluoro-benzyl)-amine (15:25)
1-Benzyl-3-methyl-1-[2-(5,6,7,8-tetrahydro-naphthalen-2-yloxy)- ethyl]-urea, (1:32), mp 135°C from methyl isocyanate and Benzyl-[2-(5,6,7,8-tetrahydro-naphthalen-2-yloxy)-ethyl]-amine (15:27)
1-Benzyl-3-methyl-1-[2-(4-cyclohexyl-phenoxy)-ethyl]-urea (1 :33), mp 90βC from methyl isocyanate and Benzyl-[2-(4-cyclohexyl-phenoxy)-ethyl]-amine (15:28)
1-Benzyl-3-methyl-1-(2-phenoxy-ethyl)-urea (1 :34), mp 88°C from methyl isocyanate and Benzyl-(2-phenoxy-ethyl)-amine (15:29) 3-Methyl-1-phenethyl-1-[2-(5,6,7,8-tetrahydro-naphthalen-2-yloxy)- ethyl]-urea, (1 :35), oil from methyl isocyanate and Phenethyl-[2-(5,6,7,8-tetrahydro-naphthalen-2-yloxy)-ethyl]-amine, (15:30)
1-(4-Fluoro-benzyl)-3-methyl-1-[2-(5,6,7,8-tetrahydro-naphthalen- 2-yloxy)-ethyl]-urea, (1:36), oil from methyl isocyanate and
(4-Fluoro-benzyl)-[2-(5,6,7,8-tetrahydro-naphthalen-2-yl oxy)-ethyl]-amine (15:31)
1 -(4-Fluoro-benzyl)-3-methyl-1 -[2-(3-trifluoromethyl-phenoxy)- ethyl]-urea, (1:37), oil from methyl isocyanate and (4-Fluoro-benzyl)-[2-(3-trifluoromethyl-phenoxy)-ethyl]-amine (15:32)
1-[2-(3,4-Dichloro-phenoxy)-ethyl]-1-(4-fluoro-benzyl)-3-methyl-urea, (1 :38), mp 178βC from methyl isocyanate and [2-(3,4-Dichloro-phenoxy)-ethyl]-(4-fluoro-benzyl)-amine (15:33)
1 -Benzyl-3-methyl-1 -[2-(naphthalen-2-yloxy)-ethyl]-urea, (1 :39), mp 95βC from methyl isocyanate and Benzyl-[2-(naphthalen-2-yloxy)-ethyl]-amine (15:34)
1-[2-(4-Benzoyl-phenoxy)-ethyl]-1-benzyl-3-methyl-urea (1:40), mp 76βC from methyl isocyanate and [4-(2-Benzylamino-ethoxy)-phenyl]-phenyl-methanone (15:35) 1 -Benzyl-1 -[2-(4-benzyl-phenoxy)-ethyl]-3-methyl-urea (1 :41 ), mp 80°C from methyl isocyanate and Benzyl-[2-(4-benzyl-phenoxy)-ethyl]-amine (15:36)
1-(4-Fluoro-benzyl)-3-methyl-1-[2-(4-nitro-phenoxy)-ethyl]-urea, (1 :42), mp 128βC from methyl isocyanate and (4-Fluoro-benzyl)-[2-(4-nitro-phenoxy)-ethyl]-amine (15:37)
1 -Benzyl-1 -[2-(2-benzyl-phenoxy)-ethyl]-3-methyl-urea (1 :43), oil from methyl isocyanate and Benzyl-[2-(2-benzyl-phenoxy)-ethyl]-amine (15:38)
1-(4-Fluoro-benzyl)-3-methyl-1-[2-(5,6,7,8-tetrahydro-naphthalen- 2-yloxy)-propyl]-urea (1 :44), oil from methyl isocyanate and
(4-Fluoro-benzyl)-[2-(5,6,7,8-tetrahydro-naphthalen-2-yl oxy)-propyl]-amine (15:39)
3-Allyl-1 -benzyl-1 -[2-(biphenyl-4-yloxy)-ethyl]-urea (1:45), mp 103°C from silyl isocyanate and benzyl-[2-(biphenyl-4-yloxy)-ethyl]-amine (15:01 )
1-[2-(3,5-Dimethoxy-phenoxy)-ethyl]-1-(3-fluoro-benzyl)-3-methyl- urea, (1 :46), oil from methyl isocyanate and [2-(3,5-Dimethoxy-phenoxy)-ethyl]-(3-fluoro-benzyl)-amine (15:41 ) 1 -Benzyl-1 -[2-(3,4-dimethoxy-phenoxy)-ethyl]-3-methyl-urea (1 :47), oil from methyl isocyanate and Benzyl-[2-(3,4-dimethoxy-phenoxy)-ethyl]-amine (15:42)
1-(3-Fluoro-benzyl)-3-methyl-1-[2-(3,4,5-trimethoxy-phenoxy)-ethyl]- urea, (1 :48), mp 147°C from methyl isocyanate and
(3-Fluoro-benzyl)-[2-(3,4,5-trimethoxy-phenoxy)-ethyl]-amine (15:43)
1 -Benzyl-1 -[2-(2,3-dimethoxy-phenoxy)-ethyl]-3-methyl-urea (1 :49), oil from methyl isocyanate and
Benzyl-[2-(2,3. dimethoxy-phenoxy)-ethyl]-amine (15:44)
1 -Benzyl-1 -[2-(17-hydroxy-13-methyl-7,8,9, 11,12,13,14,15,16,17- decahydro-6H-cyclopenta[a]phenanthren-3-yloxy)-ethyl]-3-methyl- urea, (1:50), mp 141βC from methyl isocyanate and
3-(2-Benzylamino-ethoxy)-13-methyl-7,8,9,11,12,13,14,15, 16,17-decahydro-6H-cyclopenta[a]phenanthren-17-ol (15:05)
1-Benzyl-3-ethyl-1-[2-(17-hydroxy-13-methyl-7,8,9,11,12,13,14,15,16,17, decahydro-6H-cyclopenta[a]phenanthren-3-yloxy)-ethyl]-urea, (1 :51 ) mp 133βC from ethyl isocyanate and 3-(2-Benzylamino-ethoxy)-13-methyl-7,8,9,11,12,13,14,15,
16,17-decahydro-6H-cyclopenta[a]phenanthren-17-ol (15:05) 1-Benzyl-1-[2-(17-hydroxy-13-methyl-7,8,9,11 ,12,13,14,15,16,17- decahydro-6H-cyclopenta[a]phenanthren-3-yloxy)-ethyl]-3-methyl- thiourea, (1 :52), mp 131 °C from methyl isothiocyanate and
3-(2-Benzylamino-ethoxy)-13-methyl-7,8,9,11 ,12,13, 14,15, 16,17-decahydro-6H-cyciopenta[a]phenanthren-17-ol (15:05)
1 -Benzyl-1 -[2-(4'-hydroxy-3'-bromo-biphenyl-4-yloxy)-ethyl]-3-methyl- urea, (1:53), mp 164-168βC from methyl isocyanate and benzyl-2-(4'-hydroxy-3'-bromo-biphenyl-4-yloxy)-ethyl-amine
1 -Benzyl-1 -[2-(4'-hydroxy-3'-nitro-biphenyl-4-yloxy)-ethyl]-3-methyl- urea, (1:54), mp 54-57βC, from methyl isocyanate and benzyl-2-(4'-hydroxy-3'-nitro-biphenyl-4-yloxy)-ethyl-amine
Example 2
This example illustrates the preparation of compounds of the general formula I above by reacting a secondary amine with an acylating agent such as a N,N-disubstituted carbamoyl halide. Benzyl-[2-(biphenyl-4-yloxy)-ethyl]-amine (15:01) (3.03g, 0.01 mol) is dissolved in methylene chloride (25ml) and N,N-dimethylcarbamoyl chloride (10g, 0.09mol) and triethylamine (10ml) is added.The reaction mixture is stirred for 2 days at room temperature, and 100 ml water is added dropwise. The organic phase is separated and washed with 2-M hydrochloric acid, with aqueous sodium hydrogen carbonate, dried and evaporated to dryness to give 1 -Benzyl-1 -[2-(biphenyl-4-yloxy)- -ethyl]-3,3-dimethyl-urea, (2:01 ) mp 89βC. Example 3
This example illustrates the preparation of compounds of the general formula I above by reacting a secondary amine with cyanates or isothiocyanates.
4'-(2-Benzylamino-ethoxy)-biphenyl-4-ol (15:14) (1.0g, 3.13mmol) is suspended in glacial acetic acid (10ml) and a solution of potassium cyanate (0.254g, 3.13mmol) in glacial acetic acid (10ml) is added dropwise. The reaction mixture is stirred for 1.5 hours at room temperature and poured on water at 0°C.
The precipitated product is filtered off, washed with water, and dried to give 1 -Benzyl-1 -[2-(4'-hydroxy-biphenyl-4-yloxy)-ethyl]-urea, (3:01), mp 220°C.
In essentially the same manner, the following compounds are obtained from the corresponding starting material.
1 -Benzyl-1 -[2-(biphenyl-4-yloxy)-ethyl]-urea (3:02), mp 109βC from potassium cyanate and Benzyl-[2-(biphenyl-4-yloxy)-ethyl]-amine (15:01 )
1 -Benzyl-1 -[2-(17-hydroxy-13-methyl-7,8,9,11,12,13,14,15,16,17- decahydro-6H-cyclopenta[a]phenanthren-3-yloxy)-ethyl]-urea, (3:03), mp 136βC from potassium cyanate and
3-(2-Benzylamino-ethoxy)-13-methyl-7,8,9, 11,12,13,14,15, 16,17-decahydro-6H-cyclopenta[a]phenanthren-17-ol (15:05)
1-Benzyl-1-[2-(17-hydroxy-13-methyl-7,8,9,11, 12,13,14,15,16,17- decahydro-6H-cyclopenta[a]phenanthren-3-yloxy)-ethyl]-thiourea, (3:04), mp 88βC from ammonium thiocyanate and 3-(2-Benzylamino-ethoxy)-13-methyl-7,8,9,11,12,13,14,15,
16, 17-decahydro-6H-cyclopenta[a]phenanthren-17-ol (15:05) Example 4
This example illustrates the preparation of compounds of the general formula I above by reacting a secondary amine with an acylating agent such as a chloroformate ester. Benzyl-[2-(biphenyl-4-yloxy)-ethyl]-amine (15:01) (4.7g, 16mmol) is dis¬ solved in methylene chloride (100ml) and triethylamine (10ml, 72mmol) and methyl chloroformate (2g, 20mmol) is added. The reaction mixture is stirred for 2 days at room temperature, washed with 1-M sulphuric acid, and water. The solution is dried and evaporated in vacuo to give Carbamic acid, N-[2-(biphenyl-4-yloxy]-N-benzyl methyl ester, (4:01 ), mp 60βC.
Example 5
This example illustrates the preparation of compounds of the general formula I above by reacting a carbamate of a secondary amine with an amine. N-Benzyl-N-[2-(biphenyl-4-yloxy)-ethyl] (4-nitro-phenyl) carbamate (15:02)
(1.7g, 3.6mmol) is mixed with cyclopropyl amine (3g, 55mmol) and heated at 70βC overnight. After cooling, methylene chloride (50ml) is added and the solution is washed with 2-M hydrochloric acid and water. Evaporation in vacuo and recrystalli- zation from ethyl acetate gives 1 -Benzyl-1 -[2-(biphenyl-4-yloxy)-ethyl]-3-cyclopropyl-- urea, (1 :05), mp 125°C.
In essentially the same manner, the following compounds are obtained from the corresponding starting material.
3-Allyl-1 -benzyl-1 -[2-(biphenyl-4-yloxy)-ethyl]-urea, (1 :45) mp 103βC from allyl amine and N-Benzyl-N-[2-(biphenyl-4-yloxy)-ethyl] (4-nitro-phenyl) carbamate (15:02)
Example 6
This example illustrates the preparation of compounds of the general formula I above by reacting a secondary amine with an acylating agent such as an acid halide or an acid anhydride. Benzyl-[2-(biphenyl-4-yloxy)-ethyl]-amine (15:01 ) (4.55g, 0.015mol) is dissolved in methylene chloride (100 ml) and triethylamine (2g (0.02ml) is added. Acetyl chloride (1.2g, 0.0153mol) dissolved in methylene chloride (50ml) is added dropwise. The reaction mixture is stirred overnight at room temperature, washed with 2-M hydrochloric acid and water. The solution is dried and evaporated in vacuo to give N-Benzyl-N-[2-(biphenyl-4-yloxy)-ethyl]-acetamide, (6:01 ), mp 104°C.
In essentially the same manner, the following compounds are obtained from the corresponding starting material.
N-Benzyl-N-[2-(biphenyl-4-yloxy)-ethyl]-acrylamide (6:02) mp 65βC from acryloyl chloride and Benzyl-[2-(biphenyl-4-yloxy)-ethyl]-amine (15:01 )
N-Benzyl-N-[2-(4'-hydroxy-biphenyl-4-yloxy)-ethyl]-acetamide, (6:03), mp 172βC from acetic anhydride and 4'-(2-Benzylamino-ethoxy)-biphenyl-4-ol (15:14)
N-(3-Fluoro-benzyl)-N-[2-(4'-hydroxy-biphenyl-4-yloxy)-ethyl]- acetamide, (6:04), mp 170βC from acetic anhydride and
4'-[2-(3-Fluoro-benzylamino)-ethoxy]-biphenyl-4-ol (15:20)
N-Benzyl-N-[2-(17-hydroxy-13-methyl-7,8,9, 11 ,12,13,14,15,16,17- decahydro-6H-cyclopenta[a]phenanthren-3-yloxy)-ethyl]-propionamide, (6:05), mp 130βC from propionyl chloride and
3-(2-Benzylamino-ethoxy)-13-methyl-7,8,9,11 ,12,13,14,15, 16,17-decahydro-6H-cyclopenta[a]phenanthren-17-ol (15:05) N-Benzyl-N-[2-(17-hydroxy-13-methyl-7, 8,9, 11 , 12, 13, 14,15,16,17- decahydro-6H-cyclopenta[a]phenanthren-3-yloxy)-ethyl]- acetamide, (6:06), mp 118°C from acetic anhydride and
3-(2-Benzylamino-ethoxy)-13-methyl-7,8,9, 11 ,12,13,14,15, 16,17-decahydro-6H-cyclopenta[a]phenanthren-17-ol (15:05)
1 -Benzyl-1 -[2-( 17-hydroxy-13-methyl-4-nitro-7,8,9, 11 ,12,13,14, 15,16,17-decahydro-6H-cyclopenta[a]phenanthren-3-yloxy)- ethyl]-3-acetamide, (6:07), mp 178°C from acetic anhydride and
3-(2-Benzylamino-ethoxy)-13-methyl-4-nitro-7,8,9, 11,12,13,14, 15,16,17-decahydro-6H-cyclopenta[a]phenanthren-17-ol (15:40)
Example 7
This example illustrates the preparation of compounds of the general formula I above by reacting a secondary amine with formic acid. Benzyl-[2-(biphenyl- 4-yloxy)-ethyl]-amine (15:01) (1.62g, 5.3mmol), formic acid (1.23g, 26.7mmol) and toluene (15ml) is mixed and boiled for 2 hours. The resulting solution is dried with sodium sulphate, filtered and evaporated in vacuo to dryness. Recrystallization from toluene/hexane(1:1) gives N-Benzyl-N-[2-(biphenyl-4-yloxy)-ethyl]-formamide, (7:01), mp 94βC.
Example 8
This example illustrates the preparation of compounds of the general formula I from another compound of the general formula I above.
1 -Benzyl-1 -[2-(4'-hydroxy-biphenyl-4-yloxy)-ethyl]-3-methyl-urea, (1 :15), (1.0g, 2.66mmol) is dissolved in chloroform (50 ml) by heating to about 50°C.
N-bromosuccinmide (1.0g, 5.63mmol) dissolved in warm chloroform (50ml) is added and the mixture is refluxed for 1 hour. After work up and evaporation in vacuo to dryness, the residue is recrystallized from ethanol/water(1:1), filtrered off and dried to give 1 -Benzyl-1 -[2-(4'-hydroxy-3'-bromo-biphenyl-4-yloxy)-ethyl]-3-methyl-urea, (1 :53), mp 164-168°C.
1 -Benzyl-1 -[2-(4'-hydroxy-biphenyl-4-yloxy)-ethyl]-3-methyl-urea, (1 :15), (1.0g, 2.66mmol) is dissolved in warm glacial acetic acid (15 ml). A mixture of concentrated nitric acid (0.18ml), sodium nitrite (0.72g) and water (4.3ml) is added at room temperature, and the resulting reaction mixture is stirred for 0.5 hours. After evaporation to dryness, the residue is dissolved in methylene chloride, washed with water, dried and evaporated in vacuo.The residue is recrystallized in ethyl acetate and purified by H .C to give pure 1 -Benzyl-1 -[2-(4'-hydroxy-3'-nitro-biphenyl-4-yloxy)- ethyl]-3-methyl- urea, (1:54), mp 54-57°C.
Example 9
This example illustrates the preparation of phosphoric acid esters com- pounds of the general formula I above.
1-Benzyl-1-[2-(4'-hydroxy-biphenyl-4-yloxy)-ethyl]-3-methyl-urea, (1 :15), (16.8 g, 44.6 mmol) is dissolved in pyridine (250ml) and the solution is cooled to -10βC. A mixture of phosphorus oxychloride (20 ml, 183 mmol) in pyridine (250 ml) is added dropwise at -10°C in about 30 minutes. The temperature is then kept at 0βC for one hour. The reaction mixture is then added dropwise to a mixture of water (250 ml) and ice (250 g) and left overnight at a temperature of 0°C. The solution is evaporated in vacuo to a volume of about 300 ml, pH is adjusted to 7.2 by adding 5-M aqueous sodium hydroxide, and evaporated in vacuo to a volume of 200 ml. The solution is added at -10°C to 5-M hydrochloric acid (300ml). The precipitated product is filtered off, washed with water, and dried in vacuo to give phosphoric acid, 4'-[2-(1-benzyl- 3-methyl-ureido)-ethoxy]-biphenyl- 4-ylester. The product (15g, 32.8 mmol) is con¬ verted to the sodium salt by dissolving in a mixture of methanol (225ml) and ethanol (450ml), 10-M aqueous sodium hydroxide (15ml, 150 mmol) is added drop- wise, and the precipitated product is filtered and washed with ethanol. After drying in vacuo, phosphoric acid, 4'-[2-(1-benzyl-3-methyl-ureido)-ethoxy]-biphenyl-4-ylester, sodium salt, (9:01), mp 120-122X, is obtained.
In essentially the same manner, the following compounds are obtained from the corresponding starting material. Phosphoric acid, 4'-{2-[1 -(3-fluoro-benzyl)-3-methyl-ureido]-ethoxy}-biphenyl- 4-yl ester, (9:02), mp 117-120°C from phosphorylation of 1-(3-Fluoro-benzyl)-1-[2-(4'- hydroxy-biphenyl-4-yloxy)-ethyl]-3-methyl-urea, (1 :25).
Example 10
This example illustrates the preparation of glycine esters compounds of the general formula I above. 1 -Benzyl-1 -[2-(4'-hydroxy-biphenyl-4-yloxy)-ethyl]- 3-propyl-urea,(1:23) (14.37g, 35.5 mmol) and N-(tert-butoxycarbonyl)glycine (6.22g, 35.5 mmol) is dissolved in methylene chloride (500 ml), and 4-N,N-dimethylamino- pyridine (0.1g, 0.82mmol) and N.N'-dicyclo-hexylcarbodiimide (7.7g, 37.3mmol) is added. The resulting mixture is stirred at room temperature for 6 hours, acetic acid (140 ml) is added, and the resulting precipitate is filtered off and discarded. Methane sulfonic acid (5.12g, 53.3mmol) is added and the mixture is stirred overnight. The precipitated product is filtered off and dried in vacuo to give amino-acetic acid 4'-[2-
(1-benzyl-3-propyl-ureido)-ethoxy]-biphenyl- 4-yl ester, methanesulphonate salt,(10:01), mp 115-116βC.
In essentially the same manner, the following compounds are obtained from the corresponding starting material.
Amino-acetic acid 4'-[2-(1 -benzyl-3-methyl-ureido)-ethoxy]-biphenyl- 4-yl ester, methane sulfonate, (10:02), mp 110βC from N-(tert-butoxycarbonyl)glycine and 1 -Benzyl-1 -[2-(4'-hydroxy-biphenyl-4-yloxy)-ethyl]-3-methyl-urea, (1:15)
Amino-acetic acid 4'-{2-[1 -(3-fluoro-benzyl)-3-methyl-ureido]-ethoxy}-biphenyl-4-yl ester, methane sulfonate, (10:03), mp 110-120°C from N-(tert-butoxycarbonyl)glycine and
1-(3-Fluoro-benzyl)-1-[2-(4'-hydroxy-biphenyl-4-yloxy)-ethyl]- 3-methyl-urea (1:25) Amino-acetic acid 4'-[2-(acetyl-benzyl-amino)-ethoxy]-biphenyl-4-yl ester, methane sulfonate, (10:04), mp 120-130°C from N-(tert-butoxycarbonyl)glycine and N-Benzyl-N-[2-(4'-hydroxy-biphenyl-4-yloxy)-ethyl]-acetamide, (6:03)
Amino-acetic acid 4'-{2-[acetyl-(3-fluoro-benzyl)-amino]-ethoxy}- biphenyl-4-yl ester, methane sulfonate, (10:05), mp 80-85βC from N-(tert-butoxycarbonyl)glycine and
N-(3-Fluoro-benzyl)-N-[2-(4'-hydroxy-biphenyl-4-yloxy)-ethyl]-acetamide (6:04)
Amino-acetic acid 4'-[2-(1-benzyl-3-methyl-ureido)-ethoxy]-biphenyl- 4-ylmethyl ester, methane sulfonate, (10:06), mp 25°C from N-(tert-butoxycarbonyl)glycine and
1 -Benzyl-1 -[2-(4'-hydroxymethyl-biphenyl-4-yloxy)-ethyl]-3-methyl-urea (1 :26)
Example 11 This example illustrates the preparation of carbamate esters compounds of the general formula I above.
1 -Benzyl-1 -[2-(4'-hydroxy-biphenyl-4-yloxy)-ethyl]-3-methyl-urea, (1:15) (0.2 g, 0.53 mmol), 1 ,6-dicyanatohexane (44.7 mg, 0.27 mmol), triethylamine (44.7 mg, 0.27 mmol) is dissolved in dry dimethyl formamide (3 ml) and stirred for 4 hours at room temperature. The resulting mixture is poured on ice and water, and the precipitated product is filtrered off and dried. Recrystallization from methanol gives carbamic acid, N,N'-bis-(1 ,6-hexandiyl) bis-{4'-[2-(1-benzyl-3-methyl-ureido)-ethoxy]- biphenyl-4-yl} ester, (11:01), mp 86-89βC. In essentially the same manner, the following compounds are obtained from the corresponding starting materials:
Carbamic acid, N-butyl 4'-[2-(1-benzyl-3-methyl-ureido)-ethoxy]- biphenyl-4-yl ester, (11:02), mp 105βC from n-butyl isocyanate and
1 -Benzyl-1 -[2-(4'-hydroxy-biphenyl-4-yloxy)-ethyl]-3-methyl-urea, (1 :15)
Carbamic acid, N-benzyl 4'-[2-(1-benzyl-3-methyl-ureido)-ethoxy]- biphenyl-4-yl ester, (11 :03), mp 124°C from benzyl isocyanate and 1 -Benzyl-1 -[2-(4'-hydroxy-biphenyl-4-yloxy)-ethyl]-3-methyl-urea, (1:15)
Carbamic acid, N-(4-Fluoro-phenyl) 4'-[2-(1-benzyl-3-methyl-ureido)- ethoxy]-biphenyl-4-yl ester, (11 :04), mp 156βC from 4-fluorophenyl isocyanate and 1 -Benzyl-1 -[2-(4'-hydroxy-biphenyl-4-yloxy)-ethyl]-3-methyl-urea, (1:15)
Carbamic acid, N-(l-hexyl) 4'-[2-(1-benzyl-3-methyl-ureido)-ethoxy]- biphenyl-4-yl ester, (11:05), mp 124βC from n-hexyl isocyanate and 1-Benzyl-1-[2-(4'-hydroxy-biphenyl-4-yloxy)-ethyl]-3-methyl-urea, (1:15)
Example 12
This example illustrates the preparation of carboxylic acid and carbonic acid esters compounds of the general formula I above. 1 -Benzyl-1 -[2-(4'-hydroxy-biphenyl-4-yloxy)-ethyl]-3-methyl-urea, (1 :15),
(18.94 g, 88.5 mmol) and triethylamine (16.39 g, 162 mmol) is dissolved in dry tetrahydrofurane (500 ml) and 4-chlorocarbonyl- oxy-1 -methylpiperidine 18.94g, 88.5 mmol) is added while stirring at 0βC. The resulting mixture is stirred overnight at room temperature, and aqueous sodium chloride (500 ml). The organic phase is separated, washed with aqueous sodium chloride and aqueous sodium bicarbonate, and evapo¬ rated to dryness in vacuo.
The product is converted to the hydrochloride by dissolving in ethyl acetate, drying with sodium sulphate, and adding a solution of HCl in diethylether (1.8M HCl, 30 ml). The precipitate is filtrered off, and dried in vacuo to give carbonic acid {4'-[2-(1-benzyl-3-methyl-ureido)-ethoxy]-biphenyl- 4-yl} ester (1 -methyl-piperidin-4-yl) ester, hydrochloride, (12:01 ), mp 167-169°C.
One of the starting materials used above, 4-chlorocarbonyloxy-1-methyl- piperidine, is prepared by dissolving 4-hydroxy-1-methyl-piperidine (14.4g, 125 mmol) in tetrahydrofurane (400ml) and adding phosgene (40g, 400 mmmol). The mixture is stirred overnight at room temperature, filtered, evaporated in vacuo and dried to give 4-chlorocarbonyloxy-1 -methylpiperidine.
In essentially the same manner, the following compounds are obtained from the corresponding starting materials:
But-2-enedioic acid bis-{4'-[2-(1 -benzyl-3-methyl-ureido)-ethoxy]- biphenyl-4-yl} ester, (12:02), mp 135-138βC from fumaryl chloride and
1-Benzyl-1-[2-(4'-hydroxy-biphenyl-4-yloxy)-ethyl]-3-methyl-urea, (1 :15).
Carbonic acid (4'-{2-[1 -(3-fluoro-benzyl)-3-methyl-ureido]-ethoxy}- biphenyl-4-yl) ester (1-methyl-piperidin-4-yl) ester, hydrochloride, (12:03), mp 167βC from 4-chlorocarbonyloxy-1-methyl-piperidine, and 1-(3-Fluoro-benzyl)-1-[2-(4'-hydroxy-biphenyl-4-yloxy)-ethyl]- 3-methyl-urea, (1:25)
Example 13
This example illustrates the preparation of aryl ether compounds of the general formula I above.
1 -Benzyl-1 -[2-(4'-hydroxy-biphenyl-4-yloxy)-ethyl]-3-methyl-urea, (1:15) (25.4g, 67.5mmol) is dissolved in dimethylsulfoxide (280ml) and sodium methylate (3.83g, 70.9 mmol) is added and stirred for 30 minutes. Methyl bromoacetate (10.83g, 70.8mmol) is added dropwise while cooling, and the mixture is stirred overnight at room temperature. After pouring on ice/water, the mixture is extracted with methylene chloride, and the organic phase is washed with water (3x200ml). After evaporating in vacuo, the oil obtained is dissolved in hot toluene, and left overnight at 0°C. The obtained product is filtered and dried in vacuo to give {4'-[2-(1 -Benzyl-3-methyl-ureido)- ethoxy]-biphenyl-4-yloxy}-acetic acid methyl ester, (13:01 ), mp 1 15°C.
{4'-[2-(1 -Benzyl-3-methyl-ureido)-ethoxy]-biphenyl-4-yloxy}- acetic acid methyl ester (13:01 ), is also converted by reduction with NaBH4/LiCI to 1 -Benzyl-1 - {2-[4'-(2-hydroxy-ethoxy)-biphenyl-4-yloxy]-ethyl}-3-methyl-urea, (13:02), mp 150-151 °C.
{4'-[2-(1 -Benzyl-3-methyl-ureido)-ethoxy]-biphenyl-4-yloxy}-acetic acid methyl ester, (13:01 ), is also converted by aminolysis with piperidine to 1 -Benzyl-3-methyl-1 - {2-[4'-(2-oxo-2-piperidin-1-yl-ethoxy)-biphenyl-4-yloxy]-ethyl}-urea, (13:03), mp 114°C.
(4'-[2-(1 -Benzyl-3-methyl-ureido)-ethoxy]-biphenyl-4-yloxy}-acetic acid methyl ester (13:01 ) is also converted by alkaline hydrolysis to {4'-[2-(1 -Benzyl-3-methyl- ureido)-ethoxy]-biphenyl-4-ylόxy}-acetic acid, (13:04), mp 139βC
{4'-[2-(1 -Benzyl-3-methyl-ureido)-ethoxy]-biphenyl-4-yloxy}-acetic acid methyl ester, (13:01 ), is also converted by aminolysis with N,N-dimethyl-1.2-diaminoetane to 2-{4'-[2-(1-Benzyl-3-methyl-ureido)-ethoxy]-biphenyl-4-yloxy}-N-(2-dimethylamino-ethyl)- acetamide, (13:05), mp 169βC
In essentially the same manner, the following compounds are obtained from the corresponding starting material.
1 -Benzyl-1 -[2-(4'-{2-[2-(2-{4,-[2-( 1 -benzyl-3-methyl-ureido)-ethoxy]- biphenyl-4-yloxy}-ethoxy)-ethoxy]-ethoxy}-biphenyl-4-yloxy)-ethyl]-
3-methyl-urea, (13:06), mp 151.6-151.7'C from bis-alkylation with triethylenglykol ditosylate of 1 -Benzyl-1 -[2-(4'-hydroxy-biphenyl-4-yloxy)-ethyl]-3-methyl-urea, (1 :15).
1-Benzyl-3-methyl-1-{2-[4'-(pyridin-2-ylmethoxy)-biphenyl-4-yloxy]- ethyl}-urea, (13:07), mp 145°C from alkylation with 2-(chloromethyl)pyridine of
1 -Benzyl-1 -[2-(4'-hydroxy-biphenyl-4-yloxy)-ethyl]-3-methyl-urea, (1 :15)
1 -Benzyl-1 -[2-(4'-butoxy-biphenyl-4-yloxy)-ethyl]-3-methyl-urea, (13:09), mp 104°C from alkylation with n-butyl iodide of 1 -Benzyl-1 -[2-(4'-hydroxy-biphenyl-4-yloxy)-ethyl]-3-methyi-urea, (1:15)
1 -{2-[4'-(2-Dimethylamino-ethoxy)-biphenyl-4-yloxy]-ethyl}-
1-(3-fluoro-benzyl)-3-methyl-urea, hydrochloride, (13:10), mp 118-121βC from alkylation with N-(2-chloroethyl)-dimethyl-amine of 1-(3-Fluoro-benzyl)- 1 -[2-(4'-hydroxy-bipheήyl-4-yloxy)-ethyl]-3-methyl-urea, (1 :25).
1-Benzyl-1-{2-[4'-(3-chloro-propoxy)-biphenyl-4-yloxy]-ethyl}- 3-methyl-urea (13:12) from alkylation with 1-bromo-3-chloropropane of 1-Benzyl-1-[2-(4'-hydroxy-biphenyl-4-yloxy)-ethyl]-3-methyl-urea, (1:15)
The following compounds were also obtained through alkylation reactions:
1-Benzyl-1-{2-[4'-(3-dimethylamino-propoxy)-biphenyl-4-yloxy]-ethyl}- 3-methyl-urea, (13:08), mp 205-220βC from alkylation of dimethyl amine with 1 -Benzyl-1 -{2-[4'-(3-chloro-propoxy)- biphenyl-4-yloxy]-ethyl}-3-methyl-urea (13:12)
1 -Benzyl-3-methyl-1 -{2-[4'-(3-pyrrolidin-1 -yl-propoxy)-biphenyl- 4-yloxy]-ethyl}-urea, hydrochloride, (13:11), mp 168βC from alkylation of pyrrolidine with 1 -Benzyl-1 -{2-[4'-(3-chloro-propoxy)- biphenyl-4-yloxy]-ethyl}-3-methyl-urea (13:12) Example 14
This example illustrates the preparation of glycoside derivative compounds of the general formula I above.
Beta-D-glucosepentaacetate (2.0g,5mmol) and boron trifluoride etherate (20ml) is mixed and cooled to 0°C, and 1 -Benzyl-1 -[2-(4'-hydroxy-biphenyl-4-yloxy)- ethyl]-3-methyl-urea, (1 :15) (1.9g, 5mmol) is added. The resulting clear solution is stirred at room temperature overnight, and added to a mixture of ice (300g) and sodium bicarbonate (70g). The mixture was filtered and extracted with methylene chloride (3x200ml). The organic phase was dried and evaporated in vacuo to give 4.3 g crude product. After purification by chromatography on silica and elution with ethyl acetate, evaporation and drying gives pure 1-Benzyl-3-methyl-1-{2-[4'-(3,4,5-triacet- oxy-6-acetoxymethyl-tetrahydro-pyran-2-beta-yloxy)-biphenyl-4-yloxy]-ethyl}-urea (14:01), mp 84-85°C
Acetic acid 3,4-diacetoxy-6-{4'-[2-(1 -benzyl-3-methyl-ureido)-ethoxy]-- biphenyl-4-yloxy}-5-carboxyoxy-tetrahydro-ρyran-2-ylmethyl ester, (14:01) (3.0g,
4.2mmol) is dissolved in 25 ml methanol and 3-M sodium hydroxide (3ml) and stirred at room temperature for 6 hours. The clear solution is evaporated in vacuo to dryness. After purification by chromatography on silica and elution with methylene chloride/- methanol (20:3), evaporation and drying gives pure 1-Benzyl-3-methyl-1-{2-[4'- -(3,4,5-trihydroxy-6-hydroxymethyl-tetrahydro-pyran-2-beta-yloxy)-biphenyl- -4-yloxy]-ethyl}-urea, (14:02), mp about 100βC.
Example 15
This example illustrates the preparation of compounds of the general formula II above.
Intermediates for 1:01 , 2:01 , 3:02, 4:01 , 1 :09, 6:01, 6:02, 1 :05, 1:45, 1 :21 , 7:01
N-Benzyl-2-(biphenyl-4-yloxy)-acetamide (17:01) (25.2g, 0.079 mol) is mixed with tetrahydrofurane (500 ml) and sodium borohydride (4.46g, 0.118 mol) is added. Borotrifluoride etherate (19.06g, 0.134mol) is added dropwise at 20βC during 20 minutes. The resulting mixture is stirred overnight at room temperature. Water (80ml) and 5-M hydrochloric acid (55ml) is added and the resulting mixture is refluxed for 2 hours. After cooling to room temperature, 10-M sodium hydroxide is added and pH is adjusted to 8.1. The tetrahydrofurane solution is separated and evaporated, and ethanol (125 mi) and water (140) ml is added. The resulting mixture is refluxed for 1 hour, cooled to room temperature, and the resulting product is filtered off, washed with water and dried to give Benzyl-[2-(biphenyl-4-yloxy)-ethyl]-amine (15:01).
Benzyl-[2-(biphenyl-4-yloxy)-ethylj-amine (15:01 ) is also converted to N-Benzyl-N-[2-(biphenyl-4-yloxy)-ethyl] (4-nitro-phenyl) carbamate (15:02) by reaction with 4-nitro-phenyl chloroformate.
In essentially the same manner, the following compounds are obtained from the corresponding starting material.
Intermediates for 1:03
[2-(Biphenyl-4-yloxy)-ethyl]-(4-methoxy-benzyl)-amine (15:03) from 2-(Biphenyl-4-yloxy)-N-(4-methoxy-benzyl)-acetamide (17:02)
Intermediates for 1:04
[2-(Biphenyl-4-yloxy)-ethyl]-phenethyl-amine (15:04) from 2-(Biphenyl-4-yloxy)-N-phenethyl-acetamide (17:03)
Intermediates for 1:50, 1:51 , 1:52, 3:04, 6:05, 6:06 3-(2-Benzylamino-ethoxy)-13-methyl-7,8,9, 11 ,12,13,14,15, 16,17-decahydro-6H-cyciopenta[a]phenanthren-17-ol (15:05), mp 149°C from
N-Benzyl-2-(17-hydroxy-13-methyl-7,8,9,11,12,13,14,15,16,17- decahydro-6H-cyclopenta[a]phenanthren-3-yloxy)-acetamide (18:12)
Intermediates for 1 :06
[2-(Biphenyl-4-yloxy)-ethyl]-(2-bromo-benzyl)-amine (15:06) from
2-(Biphenyl-4-yloxy)-N-(2-bromo-benzyl)-acetamide (17:04) Intermediates for 1 :07
[2-(Biphenyl-4-yioxy)-ethyl]-pyridin-2-ylmethyl-amine (15:07) from 2-(Biphenyl-4-yloxy)-N-pyridin-2-ylmethyl-acetamide (17:05)
Intermediates for 1 :08
[2-(Biphenyl-4-yloxy)-ethyl]-(3-nitro-benzyl)-amine (15:08) from 2-(Biphenyl-4-yloxy)-N-(3-nitro-benzyl)-acetamide (17:06)
Intermediates for 1:10
[2-(Biphenyl-4-yloxy)-ethyl]-(1-phenyl-ethyl)-amine (15:09) from 2-(Biphenyl-4-yloxy)-N-(1-phenyl-ethyl)-acetamide (17:07)
Intermediates for 1:11
[2-(Biphenyl-4-yloxy)-ethyl]-pyridin-3-ylmethyl-amine (15:10) from 2-(Biphenyl-4-yloxy)-N-pyridin-3-ylmethyl-acetamide (17:08)
Intermediates for 1:12
Benzyl-{2-[4'-(2-benzylamino-ethoxy)-biphenyl-4-yloxy]-ethyl}- amine (15:11) from N-Benzyl-2-[4'-(benzylcarbamoyl-methoxy)-biphenyl-4-yloxy]-acetamide (17:09)
Intermediates for 1 :13
[2-(Biphenyl-4-yloxy)-ethyl]-furan-2-ylmethyl-amine (15:12) from 2-(Biphenyl-4-yloxy)-N-furan-2-ylmethyl-acetamide (17:10)
Intermediates for 1:14 [2-(Biphenyl-4-yloxy)-ethyl]-thiophen-2-ylmethyl-amine (15:13) from
2-(Biphenyl-4-yloxy)-N-thiophen-2-ylmethyl-acetamide (17:11 )
Intermediates for 1 :20, 1 :23, 1 :24, 1 :15, 3:01 , 6:03 4'-(2-Benzylamino-ethoxy)-biphenyl-4-ol (15:14) from N-Benzyl-2-(4'-hydroxy-biphenyl-4-yloxy)-acetamide (17:12)
Intermediates for 1 :16 [2-(Biphenyl-4-yloxy)-ethyl]-(4-fluoro-benzyl)-amine (15:15) from 2-(Biphenyl-4-yloxy)-N-(4-fluoro-benzyl)-acetamide (17:13)
Intermediates for 1:17 [2-(Biphenyl-4-yloxy)-ethyl]-(2-fluoro-benzyl)-amine (15:16) from 2-(Biphenyl-4-yloxy)-N-(2-fluoro-benzyl)-acetamide (17:14)
Intermediates for 1:18 [2-(Biphenyl-4-yloxy)-ethyl]-(3-fluoro-benzyl)-amine (15:17) from 2-(Biphenyl-4-yloxy)-N-(3-fluoro-benzyl)-acetamide (17:15)
Intermediates for 1:19 Benzyl-[2-(4'-methoxy-biphenyl-4-yloxy)-ethyl]-amine (15:18) from N-Benzyl-2-(4'-methoxy-biphenyl-4-yloxy)-acetamide (17:16)
Intermediates for 1 :22 4'-[2-(4-Methyl-benzylamino)-ethoxy]-biphenyl-4-ol (15:19) from 2-(4'-Hydroxy-biphenyl-4-yloxy)-N-(4-methyl-benzyl)-acetamide (17:17) Intermediates for 1 :25, 6:04
4'-[2-(3-Fluoro-benzylamino)-ethoxy]-biphenyl-4-ol (15:20) from
N-(3-Fluoro-benzyl)-2-(4'-hydroxy-biphenyl-4-yloxy)-acetamide (17:18)
Intermediates for 1 :26
[4'-(2-Benzylamino-ethoxy)-biphenyl-4-yl]-methanol (15:21 ) from N-Benzyl-2-(4'-hydroxymethyl-biphenyl-4-yloxy)-acetamide (17:19)
Intermediates for 1:27
1-[4'-(2-Benzylamino-ethoxy)-biphenyl-4-yl]-ethanol (15:22) from
N-Benzyl-2-[4'-(1 -hydroxy-ethyl)-biphenyl-4-yloxy]-acetamide (17:20)
Intermediates for 1:28
{4'-[2-(3-Fluoro-benzylamino)-ethoxy]-biphenyl-4-yl}-methanol (15:23) from N-(3-Fluoro-benzyl)-2-(4'-hydroxymethyl-biphenyl-4-yloxy)-acetamide (17:21 )
Intermediates for 1:29
4'-[2-(3,5-Difluoro-benzylamino)-ethoxy]-biphenyl-4-ol (15:24) from
N-(3,5-Difluoro-benzyl)-2-(4'-hydroxy-biphenyl-4-yloxy)-acetamide (17:22)
Intermediates for 1:30
(2-{3,3'-Difluoro-4'-[2-(3-fluoro-benzylamino)-ethoxy]-biphenyl- 4-yloxy}-ethyl)-(3-fluoro-benzyl)-amine (15:25) from 2-[3,3'-Difluoro-4'-(3-fluoro-benzylcarbamoyl-methoxy)-biphenyl-
4-yloxy]-N-(3-fluoro-benzyl)-acetamide (17:23)
Intermediates for 1 :32 Benzyl-[2-(5,6,7,8-tetrahydro-naphthalen-2-yioxy)-ethyl]-amine(15:27), mp 198°C from
N-Benzyl-2-(5,6,7,8-tetrahydro-naphthalen-2-yloxy)-acetamide (17:25)
Intermediates for 1 :33
Benzyl-[2-(4-cyclohexyl-phenoxy)-ethyl]-amine (15:28) from N-Benzyl-2-(4-cyclohexyl-phenoxy)-acetamide (18:02)
Intermediates for 1 :34 Benzyl-(2-phenoxy-ethyl)-amine (15:29) from N-Benzyl-2-phenoxy-acetamide (18:03)
Intermediates for 1 :35
Phenethyl-[2-(5,6,7,8-tetrahydro-naphthalen-2-yloxy)-ethyl]-amine (15:30) from N-Phenethyl-2-(5,6,7,8-tetrahydro-naphthalen-2-yloxy)-acetamide (18:04)
Intermediates for 1:36
(4-Fluoro-benzyl)-[2-(5,6,7,8-tetrahydro-naphthalen-2-yl-oxy)-ethyl]-amine (15:31 ) from N-(4-Fluoro-benzyl)-2-(5,6,7,8-tetrahydro-naphthalen-2-yloxy)-acetamide (17:26)
Intermediates for 1 :37
(4-Fluoro-benzyl)-[2-(3-trifluoromethyl-phenoxy)-ethyl]-amine (15:32) from N-(4-Fluoro-benzyl)-2-(3-trifluoromethyl-phenoxy)-acetamide (18:05)
Intermediates for 1:38
[2-(3,4-Dichloro-phenoxy)-ethyl]-(4-fluoro-benzyl)-amine (15:33), from 2-(3,4-Dichloro-phenoxy)-N-(4-fluoro-benzyl)-acetamide (18:06)
Intermediates for 1 :39
Benzyl-[2-(naphthalen-2-yloxy)-ethyl]-amine (15:34) from
N-Benzyl-2-(naphthalen-2-yloxy)-acetamide (18:07) Intermediates for 1 :40
[4-(2-Benzylamino-ethoxy)-phenyl]-phenyl-methanone (15:35), mp 218βC (decomp) from
2-(4-Benzoyl-phenoxy)-N-benzyl-acetamide (18:08)
Intermediates for 1 :41
Benzyl-[2-(4-benzyl-phenoxy)-ethyl]-amine (15:36), mp 211 βC from
N-Benzyl-2-(4-benzyl-phenoxy)-acetamide (18:09)
Intermediates for 1:42
(4-Fluoro-benzyl)-[2-(4-nitro-phenoxy)-ethyl]-amine (15:37) from
N-(4-Fluoro-benzyl)-2-(4-nitro-phenoxy)-acetamide (17:27)
Intermediates for 1 :43
Benzyl-[2-(2-benzyl-phenoxy)-ethyl]-amine (15:38) from
N-Benzyl-2-(2-benzyl-phenoxy)-acetamide (18:10)
Intermediates for 1 :44
(4-Fluoro-benzyl)-[2-(5,6,7,8-tetrahydro-naphthalen-2-yl- oxy)-propyl]-amine (15:39) from
N-(4-Fluoro-benzyl)-2-(5,6,7,8-tetrahydro-naphthalen-2-yloxy)- propionamide (17:28) Intermediates for 6:07
3-(2-Benzylamino-ethoxy)-13-methyl-4-nitro-7, 8,9,11 ,12,13,14,15, 16,17-decahydro-6H-cyclopenta[a]phenanthren-17-ol (15:40), mp >250βC from
N-Benzyl-2-(17-hydroxy-13-methyl-4-nitro-7,8,9, 1 ,12,13,14,15,16,17- decahydro-6H-cyclopenta[a]phenanthren-3-yloxy)-acetamide (18:11 )
Intermediates for 1:46
[2-(3,5-Dimethoxy-phenoxy)-ethyl]-(3-fluoro-benzyl)-amine (15:41 ) from
2-(3,5-Dimethoxy-phenoxy)-N-(3-fluoro-benzyl)-acetamide (17:30)
Intermediates for 1 :47
Benzyl-[2-(3,4-dimethoxy-phenoxy)-ethyl]-amine (15:42) from
N-Benzyl-2-(3,4-dimethoxy-phenoxy)-acetamide (17:31 )
Intermediates for 1 :48
(3-Fluoro-benzyl)-[2-(3,4,5-trimethoxy-phenoxy)-ethyl]-amine (15:43) from
N-(3-Fluoro-benzyl)-2-(3,4,5-trimethoxy-phenoxy)-acetamide (17:32)
Intermediates for 1 :49
Benzyl-[2-(2,3-dimethoxy-phenoxy)-ethyl]-amine (15:44) from
N-Benzyl-2-(2,3-dimethoxy-phenoxy)-acetamide (17:29)
Example 16
This example further illustrates the preparation of compounds of the general formulas II above.
4-hydroxy-biphenyl (34g, 0.2mol) and potassium tert butylate (34g, 0.3mol) is added to dimethyl sulfoxide (300ml) and the mixture is stirred for 0.5 hours at room temperature. 1 -bromo-3-chloro-propane (39g, 0.25mol) is added and the reaction mixture is heated to 70°C for 20 hours. After cooling, chloroform (700ml) is added, and the solution is washed with water (6x400ml). After drying and evaporation to dryness in vacuo, hexane is added and the product crystallizes. Filtration and drying gives 4-(3-chloropropoxy)-biphenyl.
4-(3-chloropropoxy)-biphenyl (18.4g, 0.075mmol) is mixed with benzylamine (50ml) and heated to 100βC for 4 hours under nitrogen. The reaction mixture is cooled and methylene chloride (400ml) is added. The solution is washed with water (5x200ml), dried, evaporated in vacuo and dried to give benzyl-[3-(biphenyl- 4-yloxy)-propyl]-amine (16:01), mp 52βC.
Example 17
This example illustrates the preparation of compounds of the general formula III above.
Intermediates for 1 :01, 2:01, 3:02, 4:01, 1:09, 6:01 , 6:02, 1:05, 1 :45, 1:21, 7:01
4-Hydroxybiphenyl (119g, 0.700 mol) is dissolved in DMSO (1000ml) and sodium methylate (42g, 0.778 mol) is added. Ethyl bromoacetate (140g, 0.838 mol) is added dropwise during 20 min at room temperature. The resulting mixture is left overnight at room temperature, and added to distilled water (3000 ml). The resulting crystals are separated by filtering and washed with water (about 2000 ml). The product obtained is dried to give biphenyl-4-yloxy)-acetic acid ethyl ester. Biphenyl-4-yloxy)-acetic acid ethyl ester (65g, 0.254mol) and bensylamine
(60g, 0.561 mol) is mixed and heated to 85βC under nitrogen for 4 hours. The resulting mixture is cooled to room temperature and diethyl ether is added to precipitate the products. The precipate is filtered off and suspended in 5-M hydrochloric acid (600 ml) and stirred. Undissolved product is filtered off, washed with water and dried to give N-Benzyl-2-(biphenyl-4-yloxy)-acetamide (17:01), mp 146°C.
In essentially the same manner, the following compounds are obtained from the corresponding starting material. Intermediates for 1 :03
2-(Biphenyl-4-yloxy)-N-(4-methoxy-benzyl)-acetamide (17:02), mp 158°C from (Biphenyl-4-yloxy)-acetic acid ethyl ester from 4-hydroxy-biphenyl
Intermediates for 1 :04 2-(Biphenyl-4-yloxy)-N-phenethyl-acetamide (17:03), mp 147βC from
(Biphenyl-4-yloxy)-acetic acid ethyl ester from 4-hydroxy-biphenyl
Intermediates for 1:06
2-(Biphenyl-4-yloxy)-N-(2-bromo-benzyl)-acetamide (17:04), from (Biphenyl-4-yloxy)-acetic acid ethyl ester from 4-hydroxy-biphenyl
Intermediates for 1:07 2-(Biphenyl-4-yloxy)-N-pyridin-2-ylmethyl-acetamide (17:05), mp 170°C from
(Biphenyl-4-yloxy)-acetic acid ethyl ester from 4-hydroxy-biphenyl
Intermediates for 1:08 2-(Biphenyl-4-yloxy)-N-(3-nitro-benzyl)-acetamide (17:06), from
(biphenyl-4-yloxy)-acetic acid ethyl ester from
4-hydroxy-biphenyl
Intermediates for 1 :10
2-(Biphenyl-4-yloxy)-N-(1 -phenyl-ethyl)-acetamide (17:07) from
(biphenyl-4-yloxy)-acetic acid ethyl ester from
4-hydroxy-biphenyl
Intermediates for 1 :11
2-(Biphenyl-4-yloxy)-N-pyridin-3-ylmethyl-acetamide (17:08) from
(biphenyl-4-yloxy)-acetic acid ethyl ester from
4-hydroxy-biphenyl
Intermediates for 1:12
N-Benzyl-2-[4'-(benzylcarbamoyl-methoxy)-biphenyl-4-yloxy]-acetamide (17:09) from
(4'-Ethoxycarbonylmethoxy-biphenyl-4-yloxy)-acetic acid ethyl ester from 4,4'-dihydroxy-biphenyl
Intermediates for 1 :13
2-(Biphenyl-4-yloxy)-N-furan-2-ylmethyl-acetamide (17:10), from (biphenyl-4-yloxy)-acetic acid ethyl ester from 4-hydroxy-biphenyl Intermediates for 1 :14
2-(Biphenyl-4-yloxy)-N-thiophen-2-ylmethyl-acetamide (17:11 ), from
(biphenyl-4-yloxy)-acetic acid ethyl ester from
4-hydroxy-biphenyl
Intermediates for 1:15, 1 :20, 1 :23, 1:24, 3:01 , 6:03 N-Benzyl-2-(4'-hydroxy-biphenyl-4-yloxy)-acetamide (17:12), from
(4'-hydroxy-biphenyl-4-yloxy)-acetic acid ethyl ester from
4,4'-dihydroxy-biphenyl
Intermediates for 1:16
2-(Biphenyl-4-yloxy)-N-(4-fluoro-benzyl)-acetamide (17:13), from
(biphenyl-4-yloxy)-acetic acid ethyl ester from 4-hydroxy-biphenyl
Intermediates for 1:17
2-(Biphenyl-4-yloxy)-N-(2-fluoro-benzyl)-acetamide (17:14), from (biphenyl-4-yloxy)-acetic acid ethyl ester from 4-hydroxy-biphenyl
Intermediates for 1:18 2-(Biphenyl-4-yloxy)-N-(3-fluoro-benzyl)-acetamϊde (17:15), from
(biphenyl-4-yloxy)-acetic acid ethyl ester from 4-hydroxy-biphenyl
Intermediates for 1 :19
N-Benzyl-2-(4'-methoxy-biphenyl-4-yloxy)-acetamide (17:16), from
(4'-methoxy-biphenyl-4-yloxy)-acetic acid ethyl ester from
4'methoxy-4-hydroxy-biphenyl
Intermediates for 1:22
2-(4'-Hydroxy-biphenyl-4-yloxy)-N-(4-methyl-benzyl)-acetamide (17:17), from
(biphenyl-4-yioxy)-acetic acid ethyl ester from 4,4'-dihydroxy-biphenyl
Intermediates for 1:25, 6:04
N-(3-Fluoro-benzyl)-2-(4'-hydroxy-biphenyl-4-yloxy)-acetamide (17:18), from (4'-hydroxy-biphenyl-4-yloxy)-acetic acid ethyl ester from 4,4'-dihydroxy-biphenyl
Intermediates for 1:26 N-Benzyl-2-(4'-hydroxymethyl-biphenyl-4-yloxy)-acetamide (17:19), from
(4'-hydroxymethyl-biphenyl-4-yloxy)-acetic acid methyl ester from 4'-Hydroxymethyl-biphenyl-4-ol
Intermediates for 1:27
N-Benzyl-2-[4'-(1-hydroxy-ethyl)-biphenyl-4-yloxy]-acetamide (17:20), from [4'-(1 -Hydroxy-ethyl)-biphenyl-4-yloxy]-acetic acid ethyl ester from
4'-(1 -Hydroxy-ethyl)-biphenyl-4-ol
Intermediates for 1 :28
N-(3-Fluoro-benzyl)-2-(4'-hydroxymethyl-biphenyl-4-yloxy)-acetamide (17:21 ), from
(4'-Hydroxymethyl-biphenyl-4-yloxy)-acetic acid methyl ester from 4'-Hydroxymethyl-biphenyl-4-ol
Intermediates for 1 :29
N-(3,5-Difluoro-benzyl)-2-(4'-hydroxy-biphenyl-4-yloxy)-acetamide (17:22), from (4'-Hydroxy-biphenyl-4-yloxy)-acetic acid ethyl ester from 4,4'-dihydroxy-biphenyl
Intermediates for 1 :30 2-[3,3'-Difluoro-4'-(3-fluoro-benzylcarbamoyl-methoxy)-biphenyl-
4-yloxy]-N-(3-fluoro-benzyl)-acetamide (17:23), from
(4'-Ethoxycarbonylmethoxy-3,3'-difluoro-biphenyl-4-yloxy)- acetic acid ethyl ester from
3,3'-Difluoro-biphenyl-4,4'-diol (prepared according to ref 1 )
Intermediates for 1 :32
N-Benzyl-2-(5,6,7,8-tetrahydro-naphthalen-2-yloxy)-acetamide (17:25), mp 75°C from
(5,6,7,8-Tetrahydro-naphthalen-2-yloxy)-acetic acid ethyl ester from 5,6,7,8-tetrahydro-2-naphtol
Intermediates for 1 :36
N-(4-Fluoro-benzyl)-2-(5,6,7,8-tetrahydro-naphthalen-2-yloxy)- acetamide (17:26), from
(5,6,7,8-Tetrahydro-naρhthalen-2-yloxy)-acetic acid ethyl ester from
5,6,7,8-tetrahydro-naphthol
Intermediates for 1 :42
N-(4-Fluoro-benzyl)-2-(4-nitro-phenoxy)-acetamide (17:27) from
(4-Nitro-phenoxy)-acetic acid ethyl ester from 4-nitrophenol
Intermediates for 1 :44
N-(4-Fluoro-benzyl)-2-(5,6,7,8-tetrahydro-naphthalen-2-yloxy)- propionamide (17:28), mp 75βC from
2-(5,6,7,8-Tetrahydro-naphthalen-2-yloxy)-propionic acid ethyl ester from 5,6,7, 8-tetrahydro-2-naphtol
Intermediates for 1 :49
N-Benzyl-2-(2,3-dimethoxy-phenoxy)-acetamide (17:29), from
(2,3-Dimethoxy-phenoxy)-acetic acid methyl ester from
2,3-dimethoxyphenol Intermediates for 1 :46
2-(3,5-Dimethoxy-phenoxy)-N-(3-fluoro-benzyl)-acetamide (17:30), from
(3,5-Dimethoxy-phenoxy)-acetic acid methyl ester from
3,5-dimethoxyphenol
Intermediates for 1 :47
N-Benzyl-2-(3,4-dimethoxy-phenoxy)-acetamide (17:31), from
(3,4-Dimethoxy-phenoxy)-acetic acid methyl ester from
3,4-dimethoxyphenol
Intermediates for 1:48
N-(3-Fluoro-benzyl)-2-(3,4,5-trimethoxy-phenoxy)-acetamide (17:32), from
(3,4,5-Trimethoxy-phenoxy)-acetic acid methyl ester from 3,4,5-trimethoxyphenol
Example 18
This example further illustrates the preparation of compounds of the general formula III above.
Intermediates for 1:50, 1 :51, 1:52, 3:04, 6:05, 6:06
Sodium methoxide (3.5g, 65mmol) is added to dimethyl sulfoxide (100ml), and IS-methyl^.δ.θ.n.^.lS. .IS.ie.^-decahydro-βH-cyclopentalajphenan- thren-3,17-diol (16.3g, 60mmol) is added.The methanol formed is evaporated in vacuo, and N-Benzyl-2-bromo-acetamide (16.0g, 60mmol) is added, while the temperature is kept below 45°C. The reaction mixture is kept overnight at room temperature, and then poured onto water (500ml). The crystals obtained are dissolved in chloroform and filtered through aluminium oxide (to remove unreacted 13-methyl-7, 8, 9, 11 ,12,13,- 14,15,16,17-decahydro-6H-cyclopenta[a]phenanthren-3, 17-diol).The chloroform is evaporade in vacuo and the residue is recrystallized from methanol, filtrered of och dried, to give N-Benzyl-2-(17-hydroxy-13-methyl-7,8,9,11 ,12,13,14, 15, 16,17- decahydro-6H-cyclopenta[a]phenanthren-3-yloxy)-acetamide (18:01).
In essentially the same manner, the following compounds are obtained from the corresponding starting material.
Intermediates for 1:33 N-Benzyl-2-(4-cyclohexyl-phenoxy)-acetamide (18:02)
• from
N-Benzyl-2-bromo-acetamide and 4-cyclohexyl-phenol
Intermediates for 1:34 N-Benzyl-2-phenoxy-acetamide (18:03), mp 85°C from N-Benzyl-2-bromo-acetamide and phenol
Intermediates for 1:35 N-Phenethyl-2-(5,6,7,8-tetrahydro-naphthalen-2-yloxy)-acetamide (18:04), from
2-Bromo-N-phenethyl-acetamide and 5,6,7,8-tetrahydro-naphthol
Intermediates for 1:37
N-(4-Fluoro-benzyl)-2-(3-trifluoromethyl-phenoxy)-acetamide (18:05), from 2-Bromo-N-(4-fluoro-benzyl)-acetamide and
3-trifluoromethylphenol
Intermediates for 1 :38
2-(3,4-Dichloro-phenoxy)-N-(4-fluoro-benzyl)-acetamide (18:06), from
2-Bromo-N-(4-fluoro-benzyl)-acetamide and 3,4-dichloro-phenol
Intermediates for 1 :39
N-Benzyl-2-(naphthalen-2-yloxy)-acetamide (18:07), mp 117°C from
N-Benzyl-2-bromo-acetamide and
2-naphtol
Intermediates for 1 :40
2-(4-Benzoyl-phenoxy)-N-benzyl-acetamide (18:08), mp 129βC from
N-Benzyl-2-bromo-acetamide and
4-hydroxy-benzophenone
Intermediates for 1 :41
N-Benzyl-2-(4-benzyl-phenoxy)-acetamide (18:09), mp 106βC from
N-Benzyl-2-bromo-acetamide and 4-hydroxy-diphenylmethane
Intermediates for 1 :43
N-Benzyl-2-(2-benzyl-phenoxy)-acetamide (18:10), mp 72βC from
N-Benzyl-2-bromo-acetamide and
2-hydroxy-diphenylmethane
Intermediates for 1:57
N-Benzyl-2-(17-hydroxy-13-methyl-4-nitro-7,8,9,11, 12,13,14,15,16,17- decahydro-6H-cyclopenta[a]phenanthren-3-yloxy)-acetamide (18:11), from N-Benzyl-2-bromo-acetamide and
13-methyl*4-nitro-7,8,9,11,12,13,14,15,16,17- decahydro-6H-cyclopenta[a]phenanthren-3, 17-diol
Intermediates for 1:50, 1:51 , 1:52, 3:04, 6:05, 6:06
N-Benzyl^ -hydroxy-IS-methyl^.δ.θ.H.^.IS.^.Iδ.ie,^- decahydro-6H-cyclopenta[a]phenanthren-3-yloxy)-acetamide (18:12) from N-Benzyl-2-bromo-acetamide and
13-methyl-7,8,9,11, 12,13,14,15,16,17- decahydro-6H-cyclopenta[a]phenanthren-3, 17-diol
Example 19. Assay for anti-tumour activity in vivo This example illustrates the effect of compounds of the present invention in inhibiting in vivo tumors, measured as described below (Ref 2).
The AT-I hormone insensitive prostate adenocarcinoma which arose spontaneously from the hormone sensitive R3327 rat prostate tumour was used to assess anti-tumour activity in vivo. All experiments were carried out in Copenhagen/Fischer F, rats.
The tumour is transplanted s.c. in the flank of the animals and allowed to grow for approximately 10 days when animals are placed in groups of 6 to obtain the same mean starting volume of approximately 300 mm3 (< 2 % difference) in each group i.e. advanced established tumour.
The volume is calculated from vernier caliper measurements as follows:
length x width x depth x pi/6.
Treatment is started on day 11 and extends for 4 or 7 days, tumour growth measurements and body weights are taken on day 17 and 27. On the last day the animals are asphyxiated, the tumour weighed and gross pathology carried out.
The data given is the maximum tumour inhibition found at day 27, this is calculated from the tumour volume in the treated group as a percentage of tumour volume in the controls (T/C %).
Drugs were given either i.p. or p.o.
Compound Adm Treatm Tumour inhibition Dose route days % μmol/kg
1 -Benzyl-1 -[2-(biphenyl-4-yloxy)-ethyl]-3-methyl-urea (1:01) s.c. 4 38 64
1 -(4-Fluoro-benzyl)-3-methyl-1 -[2-(5,6,7,8-tetrahydro-naphthalen-
2-yloxy)-ethyl]-urea (1:36) i.p. 4 45 128
Amino-acetic acid 4'-[2-(1 -benzyl-3-methyl-ureido)-ethoxy]-biphenyl- 4-yl ester (10:02) p.o. 4 30 512 1-Benzyl-3-methyl-1-{2-[4'-(pyridin-2-ylmethoxy)-biphenyl-4-yloxy]- ethyl}-urea (13:07) p.o. 7 30 128
Amino-acetic acid 4'-{2-[1-(3-fluoro-benzyl)-3-methyl-ureido]-ethoxy}- biphenyl-4-yl ester, methane sulfonate (10:03) p.o. 7 66 256
Amino-acetic acid 4'-[2-(acetyl-benzyl-amino)-ethoxy]-biphenyl-4-yl ester, methane sulfonate (10:04) p.o. 7 32 256
Carbonic acid {4'-[2-(1 -benzyl-3-methyl-ureido)-ethoxy]-biphenyl-4-yl} ester (1-methyl-piperidin-4-yl) ester, hydrochloride (12:01) p.o. 7 29 256
Carbonic acid (4'-{2-[1 -(3-fluoro-benzyl)-3-methyl-ureido]-ethoxy}- biphenyl-4-yl) ester (1 -methyl-piperidin-4-yl) ester, hydrochloride (12:03) p.o. 7 81 128
Phosphoric acid, 4'-{2-[1 -(3-fluoro-benzyl)-3-methyl-ureido]-ethoxy}- biphenyl-4-yl ester (9:02) p.o. 7 50 128
Phosphoric acid, 4'-[2-(1-benzyl-3-methyl-ureido)-ethoxy]-biphenyl-
4-ylester, sodium salt (9:01) p.o. 7 48 256
Compounds of general formula (III):
N-Benzyl-2-(1-tetralon-6-yloxy)-acetamide (18:13) i.p. 4 45 128 N-Benzyl-2-(5,6,7,8-tetrahydro-naphthalen-2-yloxy)-acetamide (17:25) i.p. 4 38 128
Example 20. Assay for cytotoxicity in vitro
This example illustrates the effect of compounds of the present invention in inhibiting the growth of tumour cells (Ref 2).
Cell culture: The DU 145 cell line, derived from a metastatic brain lesion of a human prostate adenocarcinoma is purchased from American Type Culture Collection (ATCC). The DU 145 cells grow as a monolayer in RPMI 1640 medium supplemented with 10 % heat inactivated fetal calf serum (FCS) 2 mM L-glutamine, 120 units/ml penicillin and 120 ug/ml streptomycin (GIBCO) in a 5 % CO2 humidified atmosphere at 37 C.
Assay for cytotoxicity: The cytotoxic effects on survival of DU 145 cells are determined by using a colony forming assay. Logarithmically growing cells were diluted, and seeded in 5 ml petri dishes at a concentration of 210 cells/ml with a plating efficiency of approximately 20 %. 24 h later the dishes are randomly divided into groups of 3 prior to treatment with drug for 24 h. Thereafter, the cells are incubated for another 11 days with a change of medium at day 7, fixed in 100% methanol, stained with 1.0% methylene blue, and colonies composed of more than 50 cells are scored. Results are presented as percentage survival compared to non-treated cells, for each dose used of the test compounds, and these results are then used to calculate an IC50 value, i.e. the dose needed to give a 50% cell kill.
Compound name IC50 μM
N-Benzyl-N-[2-(17-hydroxy-13-methyl-7,8,9, 11 ,12,13,14,15,16,17-deca- hydro-6H-cyclopenta[a]phenanthren-3-yloxy)-ethyl]-propionamide (6:05)
0.91
N-Benzyl-N-[2-(17-hydroxy-13-methyl-7,8,9,11,12,13,14,15,16,17- decahydro-6H-cyclopenta[a]phenanthren-3-yloxy)-ethyl]-acetamide (6:06)
1.29
1 -Benzyl-1 -[2-(17-hydroxy-13-methyl-7, 8,9,11,12,13,14,15,16,17- decahydro-6H-cyclopenta[a]phenanthren-3-yloxy)-ethyl]-3-methyl-urea, (1 :50) 0.51
1-Benzyl-3-methyl-1-[2-(5,6,7,8-tetrahydro-naphthalen-2-yloxy)- ethyl]-urea, (1:32)
4.69
1 -Benzyl-1 -[2-(17-hydroxy-13-methyl-7,8,9, 11,12,13,14,15,16,17- decahydro-6H-cyclopenta[a]phenanthren-3-yloxy)-ethyl]-3-methyl-thiourea (1:52)
6.59
1-Benzyl-1-[2-(17-hydroxy-13-methyI-7,8,9,11,12,13,14,15,16,17-deca- hydro-6H-cyclopenta[a]phenanthren-3-yloxy)-ethyl]-thiourea (3:04)
7.36
-Benzyl-3-ethyl-1-[2-(17-hydroxy-13-methyl-7,8,9,11,12,13,14,15, 16,17-decahydro-6H-cyclopenta[ajphenanthren-3-yloxy)-ethyl]-urea (1 :51)
0.75 1-Benzyl-3-methyl-1-[2-(4-cyclohexyl-phenoxy)-ethyl]-urea, (1 :33)
6.99
1 -Benzyl-1 -[2-(biphenyl-4-yloxy)-ethyl]-3-methyi-urea, (1 :01) 0.66
1 -Benzyl-3-methyl-1 -(2-phenoxy-ethyl)-urea, (1 :34)
19.46
3-Methyl-1 -phenethyl-1 -[2-(5,6,7,8-tetrahydro-naphthalen-2-yloxy)- ethyl]-urea, (1 :35)
19.47
1-(4-Fluoro-benzyl)-3-methyl-1-[2-(5,6,7,8-tetrahydro-naphthalen- 2-yloxy)-ethyl]-urea, (1 :36)
9.04
1 -Benzyl-3-methyl-1 -[2-(naphthalen-2-yloxy)-ethyl]-urea (1 :39)
14.52
1 -[2-(4-Benzoyl-phenoxy)-ethyl]-1 -benzyl-3-methyl-urea (1 :40)
2.52
1 -Benzyl-1 -[2-(4-benzyl-phenoxy)-ethyl]-3-methyl-urea (1:41) 1.43
1 -Benzyl-1 -[3-(biphenyl-4-yloxy)-propyl]-3-methyl-urea (1 :02)
9.84
1 -Benzyl-1 -[2-(2-benzyl-phenoxy)-ethyl]-3-methyl-urea (1 :43)
18.46 1 -[2-(Biphenyl-4-yloxy)-ethyl]-1 -(2-bromo-benzyl)-3-methyl-urea (1 :06)
3.75
1-[2-(Biphenyl-4-yloxy)-ethyl]-3-methyl-1-pyridin-2-ylmethyl-urea (1 :07)
1.10
1-[2-(Biphenyl-4-yloxy)-ethyl]-3-methyl-1-(3-nitro-benzyl)-urea (1 :08)
3.89
1 -[2-(Biphenyl-4-yloxy)-ethyl]-3-methyl-1 -(1 -phenyl-ethyl)-urea (1 :10)
0.48
1-[2-(Biphenyl-4-yloxy)-ethyl]-3-methyl-1-pyridin-3-ylmethyl-urea (1:11)
8.22
1 -Benzyl-3-methyl-1 -[2-(4-styryl-phenoxy)-ethyl]-urea (1 :45)
15.80
1 -Benzyl-1 -(2-{4'-[2-(1-benzyl-3-methyl-ureido)-ethoxy]-biphenyl- 4-yloxy}-ethyl)-3-methyl-urea (1:12)
0.41
1-[2-(Biphenyl-4-yloxy)-ethyl]-1-furan-2-ylmethyl-3-methyl-urea (1 :13)
4.87
1-[2-(Biphenyl-4-yloxy)-ethyl]-3-methyl-1-thiophen-2-ylmethyl-urea (1:14)
1.47
1 -Benzyl-1 -[2-(4'-hydroxy-biphenyl-4-yloxy)-ethyl]-3-methyl-urea (1:15) 0.54
1-[2-(Biphenyl-4-yloxy)-ethyl]-1-(4-fluoro-benzyl)-3-methyl-urea (1:16)
0.65 N-Benzyl-N-[2-(biphenyl-4-yloxy)-ethyl]-acetamide (6:01 )
1.08
N-Benzyl-N-[2-(biphenyl-4-yloxy)-ethyl]-acryiamide (6:02)
0.48
1-[2-(1-Benzyl-3-methyl-ureido)-ethyl]-1-biphenyl-4-yl-3-methyl-urea (1 :17)
0.52
1-[2-(Biphenyl-4-yloxy)-ethyl]-1-(3-fluoro-benzyl)-3-methyl-urea (1 :18)
0.39
3-Allyl-1 -benzyl-1 -[2-(biphenyl-4-yloxy)-ethyl]-urea (1 :45) 4.18
1 -Benzyl-1 -[2-(4'-methoxy-biphenyl-4-yloxy)-ethyl]-3-methyl-urea (1 :19)
0.21
Amino-acetic acid 4'-[2-(1-benzyl-3-methyl-ureido)-ethoxy]-biphenyl-
4-yl ester (10:02)
0.45
Carbamic acid, N-methyl 4'-[2-(1-benzyl-3-methyl-ureido)-ethoxy]- biphenyl-4-yl ester (1 :20)
0.61
Carbamic acid, N-butyl 4'-[2-(1-benzyl-3-methyl-ureido)-ethoxy]- biphenyl-4-yl ester (11:02) 0.47 1-[2-(4'-Hydroxy-biphenyl-4-yloxy)-ethyl]-3-methyl- 1-(4-methyl-benzyl)-urea (1 :22)
3.54
{4'-[2-(1-Benzyl-3-methyl-ureido)-ethoxy]-biphenyi-4-yloxy}-acetic acid methyl ester (13:01)
0.93
Carbamic acid, N,N'-bis-(1,6-hexandiyl) bis-{4'-[2-(1-benzyl- 3-methyl-ureido)-ethoxy]-biphenyl-4-yl} ester (11:01)
0.98
But-2-enedioic acid bis-{4'-[2-(1 -benzyl-3-methyl-ureido)-ethoxy]- biphenyl-4-yl} ester (12:02) 0.29
1 -Benzyl-1 -[2-(4,-{2-[2-(2-{4,-[2-(1 -benzyl-3-methyl-ureido)-ethoxy]- biphenyl-4-yloxy}-ethoxy)-ethoxy]-ethoxy}-biphenyl-4-yloxy)-ethyl]- 3-methyl-urea (13:06) 4.27
1 -Benzyl-1 -[2-(4'-hydroxy-biphenyl-4-yloxy)-ethyl]-3-propyl-urea (1:23)
3.00
1-Benzyl-3-ethyl-1-[2-(4'-hydroxy-biphenyl-4-yloxy)-ethyl]-urea (1 :24)
0.72
1 -Benzyl-1 -[2-(4'-hydroxy-biphenyl-4-yloxy)-ethyl]-urea (3:01 )
6.97
Amino-acetic acid 4'-[2-(1 -benzyl-3-propyl-ureido)-ethoxy]-biphenyl- 4-yl ester (10:01)
2.45 1-Benzyl-3-methyl-1-{2-[4'-(pyridin-2-ylmethoxy)-biphenyl-4-yloxy]- ethyl}-urea (13:07)
0.48
1 -Benzyl-3-methyl-1 -{2-[4'-(2-oxo-2-piperidin-1 -yl-ethoxy)-biphenyl- 4-yloxy]-ethyl}-urea (13:03)
1.42
1 -Benzyl-1 -{2-[4'-(3-dimethylamino-propoxy)-biphenyl-4-yloxy]-ethyl}-
3-methyl-urea (13:08)
0.48
Carbamic acid, N-benzyl 4'-[2-(1-benzyl-3-methyl-ureido)-ethoxy]- biphenyl-4-yl ester (11 :03)
0.53
1 -Benzyl-1 -[2-(4'-hydroxy-3'-bromo-biphenyl-4-yloxy)-ethyl]-3-methyl-urea (1 :53)
0.36
Carbamic acid, N-(4-Fluoro-phenyl) 4'-[2-(1-benzyl-3-methyl-ureido)- ethoxy]-biphenyl-4-yl ester (11:04)
0.42
Amino-acetic acid 4'-{2-[1-(3-fluoro-benzyl)-3-methyl-ureido]-ethoxy}- biphenyl-4-yl ester, methane sulfonate (10:03)
0.29
Amino-acetic acid 4'-[2-(acetyl-benzyl-amino)-ethoxy]-biphenyl-4-yl ester, methane sulfonate (10:04)
1.96 1 -Benzyl-1 -{2-[4'-(2-hydroxy-ethoxy)-biphenyl-4-yloxy]-ethyl}- 3-methyl-urea (13:02)
0.34
Carbonic acid {4'-[2-(1-benzyl-3-methyl-ureido)-ethoxy]-biphenyl-4-yl} ester (1 -methyi-piperidin-4-yl) ester, hydrochloride (12:01)
0.47
1-(3-Fluoro-benzyl)-1-[2-(4'-hydroxy-biphenyl-4-yloxy)-ethyl]- 3-methyl-urea (1:25)
0.21
N-Benzyl-N-[2-(4'-hydroxy-biphenyl-4-yloxy)-ethyl]-acetamide (6:03)
0.72
N-(3-Fluoro-benzyl)-N-[2-(4'-hydroxy-biphenyl-4-yloxy)-ethyl]- acetamide (6:04)
0.67
Amino-acetic acid 4'-{2-[acetyl-(3-fluoro-benzyl)-amino]-ethoxy}- biphenyl-4-yl ester (10:05)
0.28
2-{4,-[2-(1-Benzyl-3-methyl-ureido)-ethoxy]-biphenyl-4-yloxy}- N-(2-dimethylamino-ethyl)-acetamide (13:05)
3.64
1 -Benzyl-1 -[2-(4'-butoxy-biphenyl-4-yloxy)-ethyl]-3-methyl-urea (13:09)
5.46
1 -Benzyl-1 -[2-(4'-hydroxy-3'-nitro-biphenyl-4-yloxy)-ethyl]-3-methyl-urea (1:54)
0.30 Carbamic acid, N-(l-hexyl) 4'-[2-(1-benzyl-3-methyl-ureido)-ethoxy]- biphenyi-4-yl ester (11 :05)
0.56
1 -Benzyl-1 -[2-(4'-hydroxymethyl-biphenyl-4-yloxy)-ethyl]-3-methyi-urea (1 :26)
0.98
Amino-acetic acid 4'-[2-(1 -benzyl-3-methyl-ureido)-ethoxy]-biphenyl- 4-ylmethyl ester (10:06) 0.87
1 -Benzyl-1 -{2-[4'-(1-hydroxy-ethyl)-biphenyl-4-yloxy]-ethyl}- 3-methyl-urea (1 :27)
0.84
Carbonic acid (4'-{2-[1 -(3-fluoro-benzyl)-3-methyl-ureido]-ethoxy}- biphenyl-4-yl) ester (1-methyl-piperidin-4-yl) ester, hydrochloride (12:03)
0.07
Phosphoric acid, 4'-{2-[1 -(3-fluoro-benzyl)-3-methyl-ureido]-ethoxy}- biphenyl-4-yl ester (9:02)
1.67
Phosphoric acid, 4'-[2-(1-benzyl-3-methyl-ureido)-ethoxy]-biphenyl-
4-ylester, sodium salt (9:01)
2.46
1-(3-Fluoro-benzyl)-1-[2-(4'-hydroxymethyl-biphenyl-4-yloxy)-ethyl]-
3-methyl-urea (1 :28)
0.15 1-(3,5-Difluoro-benzyl)-1-[2-(4'-hydroxy-biphenyl-4-yloxy)-ethyl]- 3-methyl-urea (1 :29)
1.52
1 -[2-(3,3'-Difluoro-4'-{2-[1 -(3-fluoro-benzyl)-3-methyl-ureido]- ethoxy}-biphenyl-4-yloxy)-ethyl]-1 -(3-fluoro-benzyl)-3-methyl-urea (1 :30)
0.25
1-{2-[4'-(2-Dimethylamino-ethoxy)-biphenyl-4-yloxy]-ethyl}- 1-(3-fluoro-benzyl)-3-methyl-urea, hydrochloride (13:10)
0.73
1 -Benzyl-3-methyl-1 -{2-[4'-(3-pyrrolidin-1 -yl-propoxy)-biphenyl- 4-yloxy]-ethyl}-urea, hydrochloride (13:11) 2.29
1 -Benzyl-3-methyl-1 -{2-[4'-(3,4,5-triacetoxy-6-acetoxymethyl- tetrahydro-pyran-2-beta-yloxy)-biphenyl-4-yloxy]-ethyl}-urea (14:01)
0.12
1 -Benzyl-3-methyl-1 -{2-[4'-(3,4,5-trihydroxy-6-hydroxymethyl- tetrahydro-pyran-2-beta-yloxy)-biphenyl-4-yloxy]-ethyl}-urea (14:02)
0.37
Example 21. Assay for mitosis inhibition in vitro.
This example illustrates the effect of compounds of the present invention in causing a metaphase block, which prevents normal cell division. (Ref 4).
Mitotic index. DU 145 cells were suspended as above and diluted to 105 cells/ml. Culture flasks were inoculated with 5 ml of the cell suspension and incubated for 2 days. Thereafter, cells were exposed to drug for 26 h and preparation for mitotic index analysis was carried out as previously described, except that colcemid was omitted (Ref 5 ). At each drug concentration 4000 cells (for control 8000 cells) were counted. The results are given as percentage of mitotic cells in treated cultures over percentage of mitotic cells in the control (T/C).
Compound name
Mit.lndex
T/C dose μM
N-Benzyl-N-[2-(17-hydroxy-13-methyl-7,8,9,11 ,12,13,14,15,16,17- decahydro-6H-cyclopenta[a]phenanthren-3-yloxy)-ethyl]- acetamide (6:06)
14 14.04
1 -Benzyl-1 -[2-(17-hydroxy-13-methyl-7,8,9,11 , 12,13,14,15,16,17- decahydro-6H-cyclopenta[a]phenanthren-3-yloxy)-ethyl]-3-methyl- urea (1 :50) 8 0.24
1 -Benzyl-1 -[2-(biphenyl-4-yloxy)-ethyl]-3-methyl-urea (1:01) 19 1.0
1-Benzyl-3-methyl-1-[2-(naphthalen-2-yloxy)-ethyl]-urea (1:39)
9 4.85
1 -Benzyl-1 -[3-(biphenyl-4-yloxy)-propyl]-3-methyl-urea (1 :02) 18 3.68
1 -Benzyl-1 -[2-(2-benzyl-phenoxy)-ethyl]-3-methyl-urea (1:43) 15 6.91
1-[2-(Biphenyl-4-yloxy)-ethyl]-1-(2-bromo-benzyl)-3-methyl-urea (1 :06) 14 3.75
1 -[2-(Biphenyl-4-yloxy)-ethyl]-3-methyl-1 -pyridin-2-ylmethyl-urea (1 :07) 11 2.2 1-[2-(Biphenyl-4-yloxy)-ethyl]-3-methyl-1-(3-nitro-benzyl)-urea (1 :08) 12 7.78
1-[2-(Biphenyl-4-yloxy)-ethyl]-3-methyl-1-pyridin-3-ylmethyl-urea (1 :11 ) 11 16.44
1 -Benzyl-3-methyl-1 -[2-(4-styryl-phenoxy)-ethyl]-urea (1 :45)
8 15.8
1 -Benzyl-1 -(2-{4'-[2-(1 -benzyl-3-methyl-ureido)-ethoxy]-biphenyl-
4-yloxy}-ethyl)-3-methyl-urea (1:12)
9 0.64
1 -[2-(Biphenyl-4-yloxy)-ethyl]-1 -furan-2-ylmethyl-3-methyl-urea (1:13) 11 4.87
1-[2-(Biphenyl-4-yloxy)-ethyl]-3-methyl-1-thiophen-2-ylmethyl-urea (1:14) 11 2.94
1-Benzyl-1-[2-(4'-hydroxy-biphenyl-4-yloxy)-ethyl]-3-methyl-urea (1:15)
11 0.61
N-Benzyl-N-[2-(biphenyl-4-yloxy)-ethyl]-acetamide (6:01 ) 13 2.16
1 -[2-(1 -Benzyl-3-methyl-ureido)-ethyl]-1 -biphenyl-4-yl-3-methyl-urea (1:17) 11 0.52
1 -[2-(Biphenyl-4-yloxy)-ethyl]-1 -(3-fluoro-benzyl)-3-methyl-urea (1 :18) 15 0.66
3-Allyl-1 -benzyl-1 -[2-(biphenyl-4-yloxy)-ethyl]-urea (1 :45) 13 4.18 1 -Benzyl-1 -[2-(4'-methoxy-biphenyl-4-yloxy)-ethyl]-3-methyl-urea (1 :19) 10 0.53
Amino-acetic acid 4'-[2-(1-benzyl-3-methyl-ureιdo)-ethoxy]-biphenyl-
4-yl ester (10:02)
12 0.61
Carbamic acid, N-methyl 4'-[2-(1-benzyl-3-methyl-ureido)-ethoxy]- biphenyl-4-yl ester (1:20)
13 0.61
Carbamic acid, N-butyl 4'-[2-(1-benzyl-3-methyl-ureido)-ethoxy]- biphenyl-4-yl ester (11:02) 15 0.65
1-[2-(4'-Hydroxy-biphenyl-4-yloxy)-ethyl]-3-methyl- 1-(4-methyl-benzyl)-urea (1:22) 14 3.54
Carbamic acid, N,N'-bis-(1,6-hexandiyl) bis^'-^l-benzyl- 3-methyl-ureido)-ethoxy]-biphenyl-4-yl} ester (11:01) 12 1.96
But-2-enedioic acid bis-{4'-[2-(1-benzyl-3-methyl-ureido)-ethoxy]- biphenyl-4-yl} ester (12:02) 11 0.54
1 -Benzyl-1 -[2-(4'-hydroxy-biphenyl-4-yloxy)-ethyl]-3-propyl-urea (1 :23) 15 3.00 1 -Benzyl-3-ethyl-1 -[2-(4'-hydroxy-biphenyl-4-yloxy)-ethyl]-urea (1 :24) 15 0.83
1 -Benzyl-1 -[2-(4'-hydroxy-biphenyl-4-yloxy)-ethyl]-urea (3:01 ) 8 6.97
Amino-acetic acid 4'-[2-(1 -benzyl-3-propyl-ureido)-ethoxy]-biphenyl- 4-yl ester (10:01)
13 2.45
i-Benzyl-3-methyl-1-{2-[4'-(2-oxo-2-piperidin-1-yl-ethoxy)-biphenyl- 4-yloxy]-ethyl}-urea (13:03) 16 1.42
1 -Benzyl-1 -{2-[4'-(3-dimethylamino-propoxy)-biphenyl-4-yloxy]-ethyl}-
3-methyl-urea (13:08)
15 0.48
Carbamic acid, N-benzyl 4'-[2-(1-benzyl-3-methyl-ureido)-ethoxy]- biphenyl-4-yl ester (11 :03)
11 0.61
Carbamic acid, N-(4-Fluoro-phenyl) 4'-[2-(1-benzy.l-3-methyl-ureido)- ethoxy]-biphenyl-4-yl ester (11:04) 16 0.84
Amino-acetic acid 4'-{2-[1 -(3-fluoro-benzyl)-3-methyl-ureido]-ethoxy}- biphenyl-4-yl ester, methane sulfonate (10:03) 14 0.94
Amino-acetic acid 4'-[2-(acetyl-benzyl-amino)-ethoxy]-biphenyl-4-yl ester, methane sulfonate (10:04) 16 1.96 1 -Benzyl-1 -{2-[4'-(2-hydroxy-ethoxy)-biphenyl-4-yloxy]-ethyl}- 3-methyl-urea (13:02)
13 0.34
Carbonic acid {4'-[2-(1 -benzyl-3-methyl-ureido)-ethoxy]-biphenyl-4-yl} ester (1 -methyl-piperidin-4-yl) ester, hydrochloride (12:01) 14 0.6
1 -(3-Fluoro-benzyl)-1 -[2-(4'-hydroxy-biphenyl-4-yloxy)-ethyl]-
'3-methyl-urea (1 :25)
13 0.7
N-Benzyl-N-[2-(4'-hydroxy-biphenyl-4-yloxy)-ethyl]-acetamide (6:03) 9 0.72
N-(3-Fluoro-benzyl)-N-[2-(4'-hydroxy-biphenyl-4-yloxy)-ethyl]-acetamide (6:04) 11 0.67
Amino-acetic acid 4'-{2-[acetyl-(3-fluoro-benzyl)-amino]-ethoxy}- biphenyl-4-yl ester (10:05)
24 0.28
2-{4'-[2-(1-Benzyl-3-methyl-ureido)-ethoxy]-biphenyl-4-yloxy}- N-(2-dimethylamino-ethyl)-acetamide (13:05)
16 3.64
1 -Benzyl-1 -[2-(4'-butoxy-biphenyl-4-yloxy)-ethyl]-3-methyl-urea (13:09) 12 5.46
1 -Benzyl-1 -[2-(4'-hydroxy-3'-nitro-biphenyl-4-yloxy)-ethyl]-3-methyl-urea (1:54) 24 0.6 Carbamic acid, N-(l-hexyl) 4'-[2-(1-benzyl-3-methyl-ureido)-ethoxy]- biphenyl-4-yl ester (11 :05)
22 0.56
1 -Benzyl-1 -[2-(4'-hydroxymethyl-biphenyl-4-yloxy)-ethyl]-3-methyl-urea (1 :26)
21 0.98
Amino-acetic acid 4'-[2-(1 -benzyl-3-methyl-ureido)-ethoxy]-biphenyl- 4-ylmethyl ester (10:06) 17 1.74
1 -Benzyl-1 -{2-[4'-(1 -hydroxy-ethyl)-biphenyl-4-yloxy]-ethyl}- 3-methyl-urea (1 :27)
17 0.84
Carbonic acid (4'-{2-[1 -(3-fluoro-benzyl)-3-methyl-ureido]-ethoxy}- biphenyl-4-yl) ester (1-methyl-piperidin-4-yl) ester, hydrochloride (12:03)
15 0.14
Phosphoric acid, 4'-{2-[1 -(3-fluoro-benzyl)-3-methyi-ureido]-ethoxy}- biphenyl-4-yl ester (9:02)
15 1.67
Phosphoric acid, 4'-[2-(1-benzyl-3-methyl-ureido)-ethoxy]-biphenyl-
4-ylester, sodium salt (9:01)
16 2.46
1-(3-Fluoro-benzyl)-1-[2-(4'-hydroxymethyl-biphenyl-4-yloxy)-ethyl]- 3-methyl-urea (1:28)
7 0.3 1-(3,5-Difluoro-benzyl)-1-[2-(4'-hydroxy-biphenyl-4-yloxy)-ethyl]- 3-methyl-urea (1 :29)
16 1.52
Example 22. Assay of microtubule depolvmerisation in cell culture This example illustrates the effect of compounds of the present invention in causing breakdown of cellular microtubules, as measured by the method of "indirect immunofluorescence" (Ref 6). Indirect Immunofluorescence: Cells are grown on 8-well plastic chamber slides (Permanox; Nunc, Denmark) for 2 days. After drug treatment, the cells are fixed for 5 min in 100% methanol at -20βC, followed by 5 min in 100% acetone at -20°C. The remaining steps are carried out at room temperature. Following fixation, the cells are washed for 10 s in PBS and 5 min in PBS/BSA (PBS with 0.2% BSA). Incubation with the primary antibodies (1:250 dilution) is carried out for 30 min and is followed by 3 washes for 10 min in PBS/BSA. Incubation with secondary antibodies (fluorescein isothiocyanate- and/or tetramethylrhodamine B isothiocyanate-conjugated antibodies diluted 1 :20) is for 30 min and is followed by 3 washes for 10 min in PBS/BSA. Coverslips are mounted using 1 mg/ml of p-phenylendiamine in PBS with 80% glycerol.
Analysis of the microtubule networks is done by visual inspection in microscope using the following grading:
0. Microtubules unaffected
1. Peripheral microtubules affected 2. Partial depolymerisation of microtubules
3. Total depolymerisation of microtubules.
The following compounds are found to induce total depolymerisation of the microtubules at the dose given below: Compound IM
Name Score (dose μM)
1 -Benzyl-1 -[2-(biphenyl-4-yloxy)-ethyl]-3-methyl-urea (1 :01)
3 4
1-[2-(Biphenyl-4-yloxy)-ethyl]-3-methyl-1-(1-phenyl-ethyl)-urea (1 :10)
3 4
1 -Benzyl-1 -(2-{4'-[2-(1 -benzyl-3-methyl-ureido)-ethoxy]-biphenyl- 4-yloxy}-ethyl)-3-methyl-urea (1:12)
3 0.25
1 -Benzyl-1 -[2-(4'-hydroxy-biphenyl-4-yloxy)-ethyl]-3-methyl-urea (1 :15)
3 0.25
N-Benzyl-N-[2-(biphenyl-4-yloxy)-ethyl]-acetamide (6:01 )
3 4
1 -[2-(1 -Benzyl-3-methyl-ureido)-ethyl]-1 -biphenyl-4-yl-3-methyl-urea (1 :17)
3 1
3-Allyl-1 -benzyl-1 -[2-(biphenyl-4-yloxy)-ethyl]-urea (1 :45) 3 16
1 -Benzyl-1 -[2-(4'-methoxy-biphenyl-4-yloxy)-ethyl]-3-methyl-urea (1:19)
3 1
Amino-acetic acid 4'-[2-(1-benzyl-3-methyl-ureido)-ethoxy]-biphenyl-
4-yl ester (10:02)
3 1 Carbamic acid, N-methyl 4'-[2-(1-benzyl-3-methyl-ureido)-ethoxy]- biphenyl-4-yl ester (1 :20)
3 1
Carbamic acid, N-butyl 4'-[2-(1-benzyl-3-methyl-ureido)-ethoxy]- biphenyl-4-yl ester (11:02)
3 1
1-[2-(4'-Hydroxy-biphenyl-4-yloxy)-ethyl]-3-methyl- 1-(4-methyl-benzyl)-urea (1 :22)
3 4
{4'-[2-(1-Benzyl-3-methyl-ureido)-ethoxy]-biphenyl-4-yloxy}- acetic acid methyl ester (13:01) 3 4
Carbamic acid, N,N'-bis-(1,6-hexandiyl) bis-^'-β-O-benzyl- 3-methyl-ureido)-ethoxy]-biphenyl-4-yl} ester (11:01)
3 64
But-2-enedioic acid bis-{4'-[2-(1 -benzyl-3-methyl-ureido)-ethoxy]- biphenyl-4-yl} ester (12:02)
3 1
1 -Benzyl-1 -[2-(4'-{2-[2-(2-{4'-[2-( 1-benzy l-3-methy l-ureido)-ethoxy ]- biphenyl-4-yloxy}-ethoxy)-ethoxy]-ethoxy}-biphenyl-4-yloxy)-ethyl]- 3-methyl-urea (13:06)
3 4
1 -Benzyl-1 -[2-(4'-hydroxy-biphenyl-4-yloxy)-ethyl]-3-propyl-urea (1:23)
3 4 1 -Benzyl-3-ethyl-1 -[2-(4'-hydroxy-biphenyl-4-yloxy)-ethyl]-urea (1 :24)
3 1
1 -Benzyl-1 -[2-(4'-hydroxy-biphenyi-4-yloxy)-ethyl]-urea (3:01 )
3 4
Amino-acetic acid 4'-[2-(1 -benzyl-3-propyl-ureido)-ethoxy]-biphenyl- 4-yl ester (10:01)
3 4
1-Benzyl-3-methyl-1-{2-[4'-(pyridin-2-ylmethoxy)-biphenyl-4-yloxy]- ethyl}-urea (13:07)
3 1
1 -Benzyl-1 -{2-[4'-(3-dimethylamino-propoxy)-biphenyl-4-yloxy]-ethyl}-
3-methyl-urea (13:08)
3 0.25
Carbamic acid, N-benzyl 4'-[2-(1-benzyl-3-methyl-ureido)-ethoxy]- biphenyl-4-yl ester (11:03)
3 1
1 -Benzyl-1 -[2-(4'-hydroxy-3'-bromo-biphenyl-4-yloxy)-ethyl]-3-methyl-urea (1:53)
3 0.25
Carbamic acid, N-(4-Fluoro-phenyl) 4'-[2-(1-benzyl-3-methyl-ureido)- ethoxy]-biphenyl-4-yl ester (11:04)
3 0.25
Amino-acetic acid 4'-{2-[1-(3-fluoro-benzyl)-3-methyl-ureido]-ethoxy}- biphenyl-4-yl ester, methane sulfonate (10:03)
3 0.25 Amino-acetic acid 4'-[2-(acetyl-benzyl-amino)-ethoxy]-biphenyl-4-yl ester, methane sulfonate (10:04)
3 1
1 -Benzyl-1 -{2-[4'-(2-hydroxy-ethoxy)-biphenyl-4-yloxy]-ethyl}-
3-methyl-urea (13:02)
3 1
Carbonic acid {4'-[2-(1 -benzyl-3-methyl-ureido)-ethoxy]-biphenyl-4-yl} ester (1-methyl-piperidin-4-yl) ester, hydrochloride (12:01)
3 0.25
1-(3-Fluoro-benzyl)-1-[2-(4'-hydroxy-biphenyl-4-yloxy)-ethyl]- 3-methyl-urea (1 :25) 3 0.25
N-Benzyl-N-[2-(4'-hydroxy-biphenyl-4-yloxy)-ethyl]-acetamide (6:03)
3 1
N-(3-Fluoro-benzyl)-N-[2-(4'-hydroxy-biphenyl-4-yloxy)-ethyl]- acetamide (6:04)
3 1
Amino-acetic acid 4'-{2-[acetyl-(3-fluoro-benzyl)-amino]-ethoxy}- biphenyl-4-yl ester (10:05)
3 0.25
2-{4'-[2-(1-Benzyl-3-methyl-ureido)-ethoxy]-biphenyl-4-yloxy}- N-(2-dimethylamino-ethyl)-acetamide (13:05) 3 1
1 -Benzyl-1 -[2-(4'-butoxy-biphenyl-4-yloxy)-ethyl]-3-methyl-urea (13:09)
3 4 1 -Benzyl-1 -[2-(4'-hydroxy-3'-nitro-biphenyl-4-yloxy)-ethyl]-3-methyl-urea (1 :54)
3 1
Carbamic acid, N-(l-hexyl) 4'-[2-(1-benzyl-3-methyl-ureido)-ethoxy]- biphenyl-4-yl ester (11 :05)
3 1
1 -Benzyl-1 -[2-(4'-hydroxymethyl-biphenyl-4-yloxy)-ethyl]-3-methyl-urea (1 :26) 3 1
1 -Benzyl-1 -{2-[4'-(1 -hydroxy-ethyl)-biphenyl-4-yloxy]-ethyl}- 3-methyl-urea (1 :27)
3 0.25
Carbonic acid (4'-{2-[1 -(3-fluoro-benzyl)-3-methyl-ureido]-ethoxy}- biphenyl-4-yl) ester (1-methyl-piperidin-4-yl) ester, hydrochloride (12:03)
3 0.25
1 -(3-Fluoro-benzyl)-1 -[2-(4'-hydroxymethyl-biphenyl-4-yloxy)-ethyl]-
3-methyl-urea (1 :28)
3 0.25
1-[2-(3,3'-Difluoro-4'-{2-[1-(3-fluoro-benzyl)-3-methyl-ureido]- ethoxy}-biphenyl-4-yloxy)-ethyl]-1-(3-fluoro-benzyl)-3-methyl- urea (1 :30)
3 0.25
1 -Benzyl-3-methyl-1 -{2-[4'-(3-pyrrolidin-1 -yl-propoxy)-biphenyl- 4-yloxy]-ethyl}-urea, hydrochloride (13:11)
3 4 1 -Benzyl-3-methyl-1 -{2-[4'-(3,4,5-triacetoxy-6-acetoxymethyl- tetrahydro-pyran-2-beta-yloxy)-biphenyl-4-yloxy]-ethyl}-urea (14:01)
3 1
1 -Benzyl-3-methyl-1 -{2-[4'-(3,4,5-trihydroxy-6-hydroxymethyl- tetrahydro-pyran-2-beta-yloxy)-biphenyl-4-yloxy]-ethyl}-urea (14:02)
3 0.25
The compounds according to the present invention may be used to treat many different forms of cancer.
The compounds according to the present invention may also be used for treating other diseases whereby an antimitotic activity is desired.
References.
Ref 1 :
Shoji T, Takehara S, Ogawa H, Fujisawa N, Osawa M Biphenyl ester derivatives as ferroelectric liquid crystals.
Jpn.Kokai Tokkyo Koho JP 01 29,342 (89 29,342) (Chem.Abstr 1 1 1 (1989):P88046p)
Ref 2: lchikawa T, Lamb J C, Christensson P I, Hartley-Asp B, Isaacs J T.
The Antitumor Effects of the Quinoline-3-carboxamide Linomide on Dunning R-3327 Rat Prostatic Cancers. Cancer Res 1992; 52: 3022-3028
Ref 3:
Hartley-Asp B and Gunnarsson PO.
Growth and cell survival following treatment with estramustine, nor-nitrogen mustard, estradiol and testosterone of a human prostatic cancer cell line (DU 145). J Urology 1982;, 127: 818-822
Ref 4:
Hartley-Asp B.
Estramustine-induced mitotic arrest in two human prostatic carcinoma cell lines DU 145 and PC-3.
The Prostate 1984; 5: 93-100.
Ref 5
Hartley-Asp B, Billstrδm A, Kruse E Identification by C-banding of two prostate tumour cell lines 1013 L and DU 145
Int. J. Cancer 44:161 - 64, 1989 Ref 6:
Dahllόf B, Billstrόm A, Cabral F and Hartley-Asp B. Estramustine depolymerizes microtubules by binding to tubulin. Cancer Res 1993; 53: 4573-4581.
Ref 7:
S. Alunni et al
Acta Chem. Scand. B 37. 47-53 (1983).
Ref 8:
Ed. H. Bundgaard "Design of Prodrugs" Elsevier 1985

Claims

1. Novel N-acyl-aminoalkyl phenyl ether compounds having the general formula (I)
Figure imgf000080_0001
wherein A is an aromatic ring such as phenyl, thienyl, furyl, pyridyl,
R„ R2 and R3 are selected from H, alkyl, halogen, electron acceptors and electron donors, m is 0, 1 or 2,
R4 is H or lower alkyl, including straight, branched saturated and unsatu- rated alkyl fragments having 1-6 carbon atoms,
R5 is NR6R7, OR8, H or lower alkyl, including straight, branched saturated and unsaturated alkyl fragments having 1-6 carbon atoms or lower cycloalkyl, inclu¬ ding saturated and unsaturated cyclic alkyl fragments having 1-6 carbon atoms,
R6 and R7 are H or lower alkyl, including straight, branched saturated and unsaturated alkyl fragments having 1-6 carbon atoms or lower cycloalkyl, including saturated and unsaturated cyclic alkyl fragments having 1-6 carbon atoms,
R8 is lower alkyl, including straight, branched saturated and unsaturated alkyl fragments having 1-6 carbon atoms or lower cycloalkyl, including saturated and unsaturated cyclic alkyl fragments having 3-6 carbon atoms, Y is O or S, n is 2 or 3,
Rg is H or lower alkyl, including straight, branched saturated and unsatu- rated alkyl fragments having 1-6 carbon atoms, X is O or S,
R10, R„ and R12 are selected from H, "alkyl", halogen, electron acceptors and electron donors or one of them may be
R13 Z - B - R14 i
wherein
Z is a bond, O, CO or CH2, and wherein B is an aromatic ring such as phenyl or pyridyl and R13, R14 and R15 are selected from H, "alkyl", halogen, electron acceptors and electron donors, with the provisio that Rs is saturated lower alkyl or saturated lower cycloalkyl when none of R10, R,, and R12 is p. Z - B - R14
R15 • and pharmaceutically acceptable salts thereof.
2. Compounds according to claim 1 wherein "alkyl" = Me, Et, i-Pr, t-Bu, CH2Ph or Ph, halogen = F, Cl, Br or I, electron acceptors = CF3, CO2Me, COPh, CHO, COOH, SO2NH2, SO2Me, CN or NO2, and electron donors = OMe, OH, OPh, SMe, NH2, NMe2 or NHAc.
3. Compounds according to claim 1 or 2 wherein
R„ R2 and R3 = H or F, R4 = H or Me, especially H, m = 1,
Y= 0,
R5 = NR6R7, whereby one of R6 and R7 isH and the othei * is Me or Et, especially Me,
Figure imgf000082_0001
n = 2,
X = O,
R10' R11 = *~* ( DΓF,
R„
R12 = Z - B - R14 in p- or m-position,
Figure imgf000082_0002
Z is a bond,
B = phenyl,
R13 and R14 = * H or F, and
R15 = H, OH or O-alkyl, especially OH.
4. Compounds according to anyone of the preceding claims, characteri¬ ze d in that two of R10, R„ and R12 together are -(CH2)4- and -(CH=CH)2-, or one of R10, R„ and R12 and one of R13, R14 and R15 together are groups such as -CH2-, - CH2CH2-, -CH2CH2-CH2- and -CH=CH-
5. Compounds according to anyone of the preceding claims, characteri¬ ze d in that two of R10, R„ and R12, together with the aromatic ring, form part of a steroid skeleton.
6. Compounds according to anyone of the preceding claims, characteri¬ ze d in that they contain salt-forming functional groups and that they also may be in the form of salts with suitable organic and inorganic ions.
7. Prodrugs, characterized in that they are metabolizable in a living body to one or more compound/compounds according to anyone of the claims 1 -6.
8. Prodrugs according to claim 7, characterized in that they are prepared using a phenolic hydroxyl group and that they are in the form of esters, carbamates, phosphates or carbohydrate conjugates.
9. Method of preparing compounds having the general formula I, c h a r a c t e r i z e d by utilizing a), when n = 2 and X is O or S, the following scheme 1 Scheme 1
Figure imgf000083_0001
Figure imgf000083_0002
Figure imgf000083_0003
Reducing agent
.
Figure imgf000083_0004
. R5CY1_3 or ReNCY (for R7=H)
Figure imgf000083_0005
wherein steps i) and ii) are alkylation reactions where L1 and L2 are suitable leaving group such as halogen, step iii) is an aminolysis reaction where M,0 is a suitable ester group such as methyl or ethyl ester, step iv) is a reduction of the amide which can be accomplished by for example using diborane generated in situ from NaBH4 and BF3-etherate and step v) is an ancylation and R5CYL3 and R6NCY are common acylating agents wherein L3 is an appropriate leaving group, e. g. halogen, whereby all other symbols have the meanings defined above; or b) the following scheme 2 Scheme 2
Figure imgf000084_0001
L4L5CY
\
Figure imgf000084_0002
HNR6R7
Figure imgf000084_0003
wherein the first step is an acylation wherein L4 and L5 are suitable leaving groups such as halogen, p-nitrophenoxy etc and in the subsequent step the leaving group is replaced by an appropriate amine, whereby all symbols have the meanings defined above: or c) the following scheme 3 Scheme 3
R
Figure imgf000085_0001
Figure imgf000085_0002
Figure imgf000085_0003
R5CYL5 or RβNCY (for R7=H)
Figure imgf000085_0004
wherein the first step is an alkylation where L4 is a suitable leaving group such as halogen or alkyl- or arylsulfonate and the subsequent acylation is the same as depicted in scheme 1 , whereby all other symbols have the meanings defined above.
10. Pharmaceutical composition containing as an active ingredient one or more of the compounds having the general formula (I), optionally together with a pharma¬ ceutically acceptable carrier and, if desired, other pharmacologically acceptable agents.
11. Pharmaceutical compositions according to claim 10 having antitumour activity.
12. Pharmaceutical compositions according to claim 10 having antimitotic activity.
13. A method for the treatment of cancer by administering to a patient suffering from or being at risk for acquiring cancer a therapeutically effective amount of a compound according to the general formula (I), optionally together with a pharma¬ ceutically acceptable carrier and, if desired, other pharmacologically acceptable agents.
14. A method for the treatment of cancer by administering to a patient suffering from or being at risk for acquiring cancer a therapeutically effective amount of prodrugs which are metabolizable in a living body to one or more compound/- compounds having the general formula (I), optionally together with a pharmaceutically acceptable carrier and, if desired, other pharmacologically acceptable agents.
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Cited By (5)

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WO2003051842A2 (en) * 2001-12-14 2003-06-26 Novo Nordisk A/S Compositions decreasing activity of hormone-sensitive lipase
US8153804B2 (en) 2005-08-02 2012-04-10 Lexicon Pharmaceuticals, Inc. Aryl pyridines and methods of their use
US10385007B2 (en) * 2016-12-09 2019-08-20 Celtaxsys, Inc. Monamine and monoamine derivatives as inhibitors of leukotriene A4 hydrolase
US11046658B2 (en) 2018-07-02 2021-06-29 Incyte Corporation Aminopyrazine derivatives as PI3K-γ inhibitors
US11926616B2 (en) 2018-03-08 2024-03-12 Incyte Corporation Aminopyrazine diol compounds as PI3K-γ inhibitors

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WO1992010468A1 (en) * 1990-12-12 1992-06-25 The Wellcome Foundation Limited Anti-atherosclerotic aryl compounds
WO1993001165A2 (en) * 1991-07-10 1993-01-21 Merck Sharp & Dohme Limited Aromatic compounds, compositions containing them and their use in therapy

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Publication number Priority date Publication date Assignee Title
WO1992010468A1 (en) * 1990-12-12 1992-06-25 The Wellcome Foundation Limited Anti-atherosclerotic aryl compounds
WO1993001165A2 (en) * 1991-07-10 1993-01-21 Merck Sharp & Dohme Limited Aromatic compounds, compositions containing them and their use in therapy

Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003051842A2 (en) * 2001-12-14 2003-06-26 Novo Nordisk A/S Compositions decreasing activity of hormone-sensitive lipase
WO2003051841A2 (en) * 2001-12-14 2003-06-26 Novo Nordisk A/S Compounds and uses thereof for decreasing activity of hormone-sensitive lipase
WO2003051842A3 (en) * 2001-12-14 2004-06-03 Novo Nordisk As Compositions decreasing activity of hormone-sensitive lipase
WO2003051841A3 (en) * 2001-12-14 2004-06-24 Novo Nordisk As Compounds and uses thereof for decreasing activity of hormone-sensitive lipase
US7067517B2 (en) 2001-12-14 2006-06-27 Nero Nordisk A/S Use of compounds for decreasing activity of hormone-sensitive lipase
US7279470B2 (en) 2001-12-14 2007-10-09 Novo Nordisk A/S Compounds and uses thereof for decreasing activity of hormone-sensitive lipase
US8153804B2 (en) 2005-08-02 2012-04-10 Lexicon Pharmaceuticals, Inc. Aryl pyridines and methods of their use
US10385007B2 (en) * 2016-12-09 2019-08-20 Celtaxsys, Inc. Monamine and monoamine derivatives as inhibitors of leukotriene A4 hydrolase
JP2020500899A (en) * 2016-12-09 2020-01-16 セルタクシス，インコーポレイテッド Monoamines and monoamine derivatives as inhibitors of leukotriene A4 hydrolase
AU2017371353B2 (en) * 2016-12-09 2022-02-03 Celltaxis, Llc Monamine and monoamine derivatives as inhibitors of leukotriene A4 hydrolase
US11926616B2 (en) 2018-03-08 2024-03-12 Incyte Corporation Aminopyrazine diol compounds as PI3K-γ inhibitors
US11046658B2 (en) 2018-07-02 2021-06-29 Incyte Corporation Aminopyrazine derivatives as PI3K-γ inhibitors

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