WO1995023143A1 - Indole derivatives as testosterone-5-alpha-reductase inhibitors - Google Patents
Indole derivatives as testosterone-5-alpha-reductase inhibitors Download PDFInfo
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- WO1995023143A1 WO1995023143A1 PCT/EP1995/000439 EP9500439W WO9523143A1 WO 1995023143 A1 WO1995023143 A1 WO 1995023143A1 EP 9500439 W EP9500439 W EP 9500439W WO 9523143 A1 WO9523143 A1 WO 9523143A1
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- 0 Cc1c(*C(c2c(*)[n](**)c3c(*)c(*)c(*)c(*)c23)=O)c(*)c(*)c(N(*)**I)c1* Chemical compound Cc1c(*C(c2c(*)[n](**)c3c(*)c(*)c(*)c(*)c23)=O)c(*)c(*)c(N(*)**I)c1* 0.000 description 7
- PRIGSCFENURBCJ-UHFFFAOYSA-N Cc(cc(cc1)C(c2c[n](C)c3ccccc23)=O)c1[N+]([O-])=O Chemical compound Cc(cc(cc1)C(c2c[n](C)c3ccccc23)=O)c1[N+]([O-])=O PRIGSCFENURBCJ-UHFFFAOYSA-N 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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Abstract
The present invention relates to compounds of formula (I) and the pharmaceutically acceptable salts thereof, wherein R is H or C1-C4 alkyl; R?1, R2, R3, R4, R5, R6 and R7¿ are each independently selected from H, C¿1?-C4 alkyl, halo(C1-C4)alkyl, C1-C4 alkoxy and halo; R?8¿ is -COOH, -COOR12 or tetrazol-5-yl; R9 is optionally substituted C¿1?-C12 alkyl,C4-C12 alkenyl, C4-C12 alkynyl or C4-C7 cycloalkyl; R?10 and R11¿, taken together, represent a group of formula (a) where W is directly attached to the substituted phenyl ring; R12 is a biolabile ester-forming group; R?13 and R14¿ are either each independently selected from H and C¿1?-C4 alkyl or, when taken together, represent C3-C6 alkylene; X is a direct link or C1-C6 alkylene; Y is C1-C6 alkylene; W is methylene, O, S, SO or SO2; and Z is methylene, -CH(C1-C4 alkyl)-, -C(C1-C4 alkyl)2-, carbonyl or thiocarbonyl together with compositions containing: processes for the preparation of, uses of and intermediates used in the preparation of, such compounds. The compounds are steroid 5α-reductase inhibitors useful for treating diseases such as benign prostactic hypertrophy.
Description
INDOLE DERIVATIVES AS TESTOSTERONE-5-ALPHA-REDUCTASE INHIBITORS This invention relates to indole derivatives which have steroid 5α-reductase inhibitory activity.
More particularly, this invention relates to indoles, their preparation and their use as testosterone-5α-reductase inhibitors.
The androgen class of steroidal hormones is responsible for the difference in the physical characteristics of males and females. Of all the organs that produce androgens, the testes produce these hormones in the greatest amounts. Over-production of these hormones in the body results in many undesirable physical manifestations and disease states, e.g. acne vulgaris, alopecia, seborrhoea, female hirsutism, benign prostatic
hypertrophy and male pattern baldness.
The principal androgen secreted by the testes is testosterone and it is the primary androgen present in male plasma. The principal mediator of androgenic activity in certain organs such as the prostate and sebaceous gland are the 5α-reduced androgens. Testosterone is therefore the prohormone of 5α-dihydrotestosterone which is formed locally in the above organs by the action of testosterone-5α-reductase, of which two isozymes are known to exist in humans, testosterone 5α-reductase-1 and testosterone 5α-reductase-2. The presence of elevated levels of dihydrotestosterone in many disease states has therefore focussed attention on the synthesis of testosterone 5α-reductase inhibitors.
Testosterone 5α-reductase inhibitors may also be useful in the treatment of human prostate adenocarcinomas.
The present invention provides compounds of the formula:-
and the pharmaceutically acceptable salts thereof,
wherein R is H or C1-C4 alkyl; R1, R2, R3, R4, R5, R6 and R7 are each independently selected from H, C1-C4 alkyl, halo(C1-C4)alkyl, C1-C4 alkoxy and halo;
R8 is -COOH, -COOR12 or tetrazol-5-yl;
R9 is C1-C12 alkyl, C4-C12 alkenyl, C4-C12 alkynyl or C4-C7 cycloalkyl, said alkyl, alkenyl, alkynyl and cycloalkyi being optionally substituted by C4-C7 cycloalkyi, halo, C1-C4 alkoxy, C1-C4 alkylamino, di(C1-C4 alkyl)amino, aryl or a heterocyclic group;
R10 and R11, taken together, represent a group of the formula:
or -CH=CH-
where W is directly attached to the substituted phenyl ring;
R12 is a biolabile ester-forming group;
R13 and R14 are either each independently selected from H and C1-C4 alkyl or, when taken together, represent C3-C6 alkylene; X is a direct link or C1-C6 alkylene;
Y is C1-C6 alkylene;
W is methylene, O, S, SO or SO2;
Z is methylene, -CH(C1-C4 alkyl)-, -C(C1-C4 alkyl)2-, carbonyl or thiocarbonyl;
"aryl", used in the definition of R9, means phenyl optionally substituted by C1-C6 alkyl, C1-C6 alkoxy, halo or halo¬
( C1-C6)alkyl; and "heterocyclic group", used in the definition of R9, means a 5- or 6-membered heterocyclic group containing 1 or 2 heteroatoms each independently selected from N, O and S, said group being optionally substituted by C1-C6 alkyl, C1-C6 alkoxy, halo(C1-C6 alkyl) or halo.
Alkyl, alkylene and alkoxy groups containing three or more carbon atoms and alkenyl and alkynyl groups containing four or more carbon atoms may be straight- or branched-chain.
The term "halo" means fluoro, chloro, bromo or iodo.
The term "biolabile ester-forming group" is well understood in medicinal chemistry as meaning a group which forms an ester which can be readily cleaved in vivo to liberate the corresponding acid of the formula (I)
wherein R8 is -COOH. A number of such ester groups are well-known, for example in the penicillin area or in the case of the angiotensin-converting enzyme (ACE) inhibitor antihypertensive agents.
Esters of the formula (I) wherein R8 is -COOR12 wherein R12 is C1-C6 alkyl are steroid 5α-reductase inhibitors per se but, in general, esters where R12 is a biolabile ester-forming group are useful as pro-drugs to provide compounds of the formula (I) wherein R8 is -COOH in vivo following oral administration. Such esters are also useful as intermediates for the preparation of compounds of the formula (I) wherein R8 is -COOH.
The suitability of any particular ester-forming group for this purpose can be assessed by conventional in vitro or in vivo enzyme hydrolysis studies.
Examples of biolabile ester-forming groups are alkyl, alkanoyloxyalkyl (including alkyl, cycloalkyi or aryl substituted derivatives thereof),
arylcarbonyloxyalkyl (including aryl substituted derivatives thereof), aryl, arylalkyl, indanyl and haloalkyl: wherein alkanoyl groups have from 2 to 8 carbon atoms, alkyl groups have from 1 to 8 carbon atoms and aryl means phenyl or naphthyl, both of which may be optionally substituted by C1-C4 alkyl, C1-C4 alkoxy or halo. Alkyl, alkanoyl and alkoxy groups can, where appropriate, be straight- or branched-chain.
Specific examples of biolabile ester-forming groups are C1-C6 alkyl (e.g. methyl, ethyl, n-propyl, isopropyl), benzyl, 1-(2,2-diethylbutyryloxy)ethyl, 2-ethylpropionyloxymethyl, 1-(2-ethylpropionyloxy)ethyl, 1-(2,4-dimethylbenzoyloxy)ethyl, α-benzoyloxybenzyl, 1-(benzoyloxy)ethyl, 2-methyl-1-propionyloxy-1-propyl, 2,4,6-trimethylbenzoyloxymethyl, 1 -(2,4,6-trimethylbenzoyloxy)ethyl, pivaloyloxymethyl, phenethyl, phenpropyl, 2,2,2-trifluoroethyl, 1- or 2-naphthyl, 2,4-dimethylphenyl, 4-t-butylphenyl and 5-indanyl.
The pharmaceutically acceptable salts of the compounds of the formula (I) include suitable acid addition and base salts thereof.
Suitable acid addition salts are formed from acids which form non-toxic salts and examples thereof are the hydrochloride, hydrobromide,
hydroiodide, sulphate, bisulphate, phosphate, hydrogen phosphate, acetate, maleate, fumarate, lactate, tartrate, citrate, giuconate, benzoate,
methanesulphonate, benzenesulphonate and para-toluenesulphonate salts.
Suitable base salts are formed from bases which form non-toxic salts and examples thereof are the calcium, lithium, magnesium, potassium, sodium, N-benzyl-N-(2-phenylethyl)amine, 1-adamantylamine and
diethanoiamine salts.
Preferred base salts are the sodium and potassium salts.
For a review on suitable pharmaceutical salts see Berge et al, J.
Pharm, Sci., 66, 1-19 (1977).
In a preferred aspect of the present invention "aryl" means phenyl optionally substituted by from 1 to 3 substituents and preferably means phenyl optionally substituted by 1 or 2 substituents.
In a further preferred aspect of the present invention, the term
"heterocyclic group" means a heteroaryl group such as pyrrolyl, furyl, thienyl, imidazolyl, thiazolyl, pyridinyl, pyrimidinyl, pyridazinyl or pyrazinyl, all of which may be optionally substituted by C1-C6 alkyl, C1-C6 alkoxy, halo or halo(C1-C6 alkyl).
In the above definitions relating to the present invention:-
Preferably R is H. Preferably R1, R2, R3, R4, R5, R6 and R7 are each H.
Preferably Rβ is -COOH or -COOR12.
Most preferably R8 is -COOH. Preferably R9 is C1-C12 alkyl optionally substituted by aryl.
More preferably R9 is C1-C8 alkyl optionally substituted by aryl.
Most preferably R9 is C1-C6 alkyl substituted by aryl.
Preferably R10 and R11, taken together, represent a group of the formula:-
Preferably R12 is C1-C6 alkyl.
Most preferably R12 is ethyl.
Preferably R13 and R14 are each independently selected from Hand C1-C4 alkyl.
Most preferably R13 and R14 are both H.
Preferably X is a direct link or C1-C3 alkylene.
More preferably X is a direct link or methylene.
Most preferably X is methylene. Preferably Y is C1-C4 alkylene.
Most preferably Y is propylene.
Preferably W is methylene or O.
Most preferably W is O.
Preferably Z is carbonyl.
Preferably "aryl" means phenyl optionally substituted by C1-C6 alkyl or halo.
More preferably "aryl" means phenyl optionally substituted by ethyl, n-propyl, isobutyl or chloro.
Most preferably "aryl" means phenyl substituted by ethyl or n-propyl.
Examples of preferred definitions of R9 are 1-(4-isobutylphenyl)ethyl, 1-(4-n-propylphenyl)butyl, 1-(4-isobutylphenyl)butyl, 1-(4-ethylphenyl)pentyl,
1-(4-n-propylphenyl)pentyl, 1-(4-n-propylpheny!)hexyl, diphenylmethyl and di(4-chlorophenyl)methyl. A particularly preferred definition of R9 is 1 -(4-ethylphenyl)pentyl or 1-(4-n-propylphenyl)pentyl.
A compound of the formula (I) may contain one or more asymmetric carbon atoms and/or one or more non-aromatic carbon-carbon double bonds and may therefore exist in two or more stereoisomeric forms. The present invention includes both the individual stereoisomers of the compounds of the formula (I) together with mixtures thereof. Separation of diastereoisomers or cis and trans isomers may be achieved by conventional techniques, e.g. by fractional crystallisation, chromatography or H.P.L.C of a stereoisomeric mixture of a compound of the formula (I) or a suitable salt or derivative thereof. An individual enantiomer of a compound of the formula (I) may also be prepared from a corresponding optically pure intermediate or by resolution, such as by H.P.L.C. of a racemate using a suitable chiral support or by fractional crystallisation of the diastereoisomeric salts formed by reaction of a racemate with a suitable optically active acid or base.
The compounds of formula (I) provided by the invention may be prepared by the following methods:-
1) The compounds of the formula (I) wherein R8 is -COOH
and X, Y, Z, R, R1 to R7 and R9 to R11 are as
previously defined for a compound of the formula (I) may be prepared by cleavage of an ester of the formula:-
A plethora of suitable ester-forming groups that may be cleaved to provide the corresponding carboxylic acid are known to the skilled person, see, e.g., T.W. Greene and P.G.M. Wuts, "Protective Groups in Organic Synthesis", Second Edition, Wiley-lnterscience (1991).
Where R15 is an ester-forming group that may be removed by hydrolysis, e.g. a biolabile ester-forming group as previously defined for R12 such as C1-C6 alkyl (i.e. a compound of the formula (I) wherein Rβ is -COOR12), the hydrolysis may be carried out under acidic or basic conditions, e.g. using an aqueous solution of either a suitable mineral acid or a suitable inorganic base. Preferably the hydrolysis is carried out under basic conditions.
In a typical procedure, an ester of the formula (II) is treated with an aqueous solution of a suitable base, e.g. sodium or potassium hydroxide, and in the presence of a suitable organic co-solvent, e.g. 1 ,4-dioxane, tetrahydrof uran or a C1-C4 alkanol (e.g. methanol or ethanol) or a combination thereof. The hydrolysis is typically carried out at from room temperature to the reflux temperature. The product is obtained as a base salt which may be converted to the carboxylic acid by acidification in the work-up procedure.
Where R15 is an ester-forming group that may be removed by reduction, e.g. benzyl, the reduction may be carried out by catalytic hydrogenation using, e.g., palladium-on-charcoal, as the catalyst.
2) The compounds of the formula (I) wherein R8 is -COOH
and X, Y, Z, R, R1 to R7 and R9 to R11 are as previously defined for a compound of the formula (I) may be prepared by hydrolysis of a compound of the formula:-
previously defined for a compound of the formula (I) and R16 and R17 are each independently selected from H and C1-C4 alkyl.
The hydrolysis may be carried out under acidic or basic conditions, e.g. using an aqueous solution of either a suitable mineral acid such as hydrochloric or sulphuric acid, or a suitable inorganic base such as sodium or potassium hydroxide, at from room temperature to the reflux temperature. When basic hydrolysis conditions are used the product is obtained as a base salt which may be converted to the carboxylic acid by acidification in the work-up procedure.
The intermediates of the formula (III) can be prepared by reaction of the corresponding esters of the formula (I) wherein RB is -COOR12 (e.g. where R12 is C1-C6 alkyl) with an amine of the formula R16R17NH wherein R16 and R17 are as previously defined for this method. The
reaction is typically carried out in a sealed reaction vessel using an excess of the amine in a suitable solvent, e.g. a C1-C4 alkanol.
3) The compounds of the formula (I) wherein R8 is -COOH
and X, Y, Z, R, R1 to R7 and R9 to R11 are as previously defined for a compound of the formula (I), may be prepared by hydrolysis of a compound of the formula:-
wherein X, Y, Z, R, R1 to R7 and R9 to R11 are as previously defined for a compound of the formula (I) and R18 is H or C1-C4 alkyl.
The hydrolysis may be carried out under acidic or basic conditions, e.g. using an aqueous solution of either a suitable acid such as hydrochloric or acetic acid, or a suitable inorganic base such as sodium or potassium hydroxide, at from room temperature to the reflux temperature. When basic hydrolysis conditions are used, the product is obtained as a base salt which may be converted to the carboxylic acid by acidification in the work-up procedure.
4) The compounds of the formula (I) wherein R8 is -COOH and X, Y, Z, R, R1 to R7 and R9 to R11 are as previously defined for a compound of the formula (I) may be prepared by hydrolysis of a compound of the formula:-
wherein X, Y, Z, R, R1 to R7 and R9 to R11 are as previously defined for a compound of the formula (I).
The hydrolysis may be carried out under acidic or basic conditions, e.g. using an aqueous solution of either a suitable acid such as hydrochloric or sulphuric acid, or a suitable inorganic base such as sodium or potassium hydroxide, at from room temperature to the reflux temperature. When basic conditions are used, hydrogen peroxide may optionally be present and also the product is obtained as a base salt which may be converted to the carboxylic acid by acidification in the work-up procedure.
5) The compounds of the formula (I) wherein R8 is -COOH and X, Y, Z, R, R1 to R7 and R9 to R11 are as previously defined for a compound of the formula (I) may be prepared by acidic hydrolysis of a compound of the formula:-
The hydrolysis may be carried out using an aqueous solution of a suitable acid, such as hydrochloric acid, at from room temperature to the reflux temperature. The compounds of the formula (I) wherein R8 is -COOR12 and X, Y, Z, R, R1 to R7 and R9 to R12 are as previously defined for a compound of the formula (I) may be prepared by esterification of a compound of the formula (I) wherein R8 is -COOH and X, Y, Z, R, R1 to R7 and R9 to R11 are as previously defined for a compound of the formula (I) with an alcohol of the formula R12OH wherein R12 is as previously defined for this method.
The reaction may be carried out under classical esterification conditions such as by using an excess of the alcohol and with acid catalysis, e.g. by sulphuric acid or p-toluenesulphonic acid, at from room temperature to the reflux temperature. The water generated during the reaction may be removed by azeotropic distillation or by the use of a dehydrating agent or a molecular sieve. The esterification may also be carried out by reacting the acid with the alcohol in the presence of a dehydrating agent, e.g.
dicyclohexylcarbodiimide or diethyiazodicarboxylate/
triphenylphosphine (see O. Mitsunobu, Synthesis, 1981, 1).
Alternatively the esterification may be carried out by first forming an activated ester or imidazolide derivative of the carboxylic acid, followed by reaction of the activated ester or imidazolide in situ with the alcohol of the formula R12OH. An activated ester may be formed by reacting the carboxylic acid with 1-hydroxybenzotriazole in the presence of a suitable dehydrating agent, e.g. 1-(3-N,N- dimethylaminopropyl)-3-ethylcarbodiimide, and in a suitable solvent, e.g. dichloromethane, at room temperature. An imidazolide may be formed by reacting the carboxylic acid with 1,1'-carbonyldiimidazole in a suitable solvent, e.g.dichloromethane, at room temperature.
7) The compounds of the formula (I) wherein R8 is -COOR12 and X, Y, Z, R, R1 to R7 and R9 to R12 are as previously defined for a compound of the formula (I) may be prepared by reaction of a compound of the formula:-
wherein X, Y, Z, R, R1 to R7 and R9 to R11 are as previously defined for a compound of the formula (I) and Z1 is a suitable leaving group, e.g. chloro or bromo (see also the activated ester and imidazolide intermediates in method (6)), with an alcohol of the formula R12OH wherein R12 is as previously defined for this method.
Where Z1 is halo, the reaction may be carried out in the presence of an acid acceptor, e.g. pyridine, and in a suitable solvent, e.g.
dichloromethane, at from 0°C to room temperature.
8) The compounds of the formula (I) wherein R8 is -COOR12 and X, Y, Z, R, R1 to R7 and R9 to R12 are as previously defined for a compound of the formula (I) may be prepared by reaction of a base salt of a compound of the formula (I) wherein R8 is -COOH and X, Y, Z, R, R1 to R7 and R9 to R11 are as previously defined for a compound of the formula (I) (i.e. a carboxylate base salt) with a compound of the formula R12Z2 wherein R12 is as previously defined for a compound of the formula (I) and Z2 is a suitable leaving group, e.g. halo, preferably bromo or iodo, or p-toluenesulphonyloxy. Preferred base salts of a compound of the formula (I) for use in this method include the sodium and potassium salts. The reaction may be carried out in a suitable solvent, e.g. dimethylformamide or tetrahydrofuran, at from room temerature to the reflux temperature.
9) All compounds of the formula (I) may be prepared by acidic hydrolysis of a compound of the formula:-
Where R8 is -COOR12, the ketal function can be selectively hydrolysed in the presence of the ester function, e.g. by using a very dilute solution of a suitable mineral acid such as hydrochloric acid.
The compounds of the formula (VIII) may be prepared by first forming the corresponding ketal of a compound of the formula (IX) wherein X, Z, R, R1 to R7 and R9 to R11 are as previously defined for this method, by reaction with the appropriate alcohol under acidic conditions, e.g. see T.W. Greene and P.G.M. Wuts, "Protective Groups in Organic
Synthesis", Second Edition, Wiley-lnterscience (1991), followed by N- alkylation of the ketal by a similar procedure to that described in method (10) for alkylation of a compound of the formula (IX). 10) All the compounds of the formula (I) wherein X, Y, Z, R and R1 to R11 are as previously defined for a compound of the formula (I) may be prepared by alkylation of a base salt (i.e. the N-deprotonated form) of a compound of the formula:-
The reaction may be performed by initial deprotonation of a
compound of the formula (IX) with a suitable base, e.g. sodium hydride or potassium carbonate, followed by reaction of the resulting anion with a compound of the formula Z3-Y-COOR12, Z3-Y-(tetrazol-5-yl) or a base salt thereof, or a base salt of a compound of the formula Z3-Y-COOH, as required. The reaction may be carried out in a suitable solvent, e.g. N,N-dimethylformamide, tetrahydrofuran or 2-butanone, at from 0°C to the reflux temperature.
Alternatively the reaction may be carried out under phase transfer conditions where a suitable base is sodium or potassium hydroxide.
Where a compound of the formula (I) wherein R8 is -COOH is required, the product is obtained as a base salt which may be converted to the carboxylic acid by acidification in the work-up procedure. Where a compound of the formula (I) wherein R8 is tetrazol-5-yl is required, the product may be obtained as a base salt which may be converted to the NH-tetrazole by acidification in the work-up procedure.
11) All the compounds of the formula (I) where X, Y, Z, R and R1 to R11 are as previously defined for a compound of the formula (I) can be prepared by N-alkylation of a base salt (i.e. at least an N- deprotonated form) of a compound of the formula:-
The reaction may be performed by initial deprotonation of a
compound of the formula (X) with a suitable base, e.g. potassium tert- butoxide, potassium carbonate or sodium hydride, followed by reaction of the resulting N-deprotonated compound with a compound of the formula R9Z4. The reaction is typically carried out in a suitable solvent, e.g. N,N-dimethylformamide, at from room temperature to the reflux temperature of the solvent.
Where a compound of the formula (I) wherein R8 is -COOH is required, the product is obtained as a base salt which may be converted to the carboxylic acid by acidification in the work-up procedure.
The starting materials of the formula (X) may be prepared by conventional procedures using similar preparative methods to those illustrated in the following Examples and Preparations sections.
12) The compounds of the formula (I) where R10 and R11, taken together, represent a group of the formula:-
W is O or S, and X, Y, Z, R, R1 to R9 and R13 and R14 are as previously defined for a compound of the formula (I), can be prepared by intramolecular cyclisation of a base salt (i.e. at least a phenoxide or thiophenoxide base salt) of a compound of the formula:-
or of a compound of the formula (XI) in the presence of an acid acceptor,
wherein X, Y, Z, R, R1 to R9 and R13 and R14 are as previously defined for this method and Z5 is a suitable leaving group, e.g. halo, preferably chloro, bromo or iodo, p-toluenesulphonyloxy or
methanesulphonyloxy.
The preferred base salts of the compounds of the formula (XI) include the alkali metal salts, e.g. the sodium and potassium salts.
Preferred acid acceptors include triethylamine and pyridine.
The reaction is typically carried out in a suitable solvent, e.g.
tetrahydrofuran or N,N dimethylformamide.
The phenoxide or thiophenoxide base salt of the compound of the formula (XI) can be generated in situ from the corresponding phenol or thiophenol by treatment with a suitable base, e.g. sodium hydride.
Such phenols and thiophenols of the formula (XI) may be prepared by conventional procedures.
Where a compound of the formula (I) wherein R8 is -COOH is required and a base salt of a compound of the formula (XI) is used, the product is obtained as a base salt which may be converted to the carboxylic acid by acidification in the work-up procedure.
13) The compounds of the formula (I) where R10 and R11, taken together, represent a group of the formula:-
wherein X, Y, R and R1 to R9 are as previously defined for this method, with a compound of the formula:-
In a typical procedure, the reaction is carried out in a suitable solvent, e.g. dichloromethane, and in the presence of an acid acceptor at from room temperature to the reflux temperature of the solvent.
The starting materials of the formulae (XII) and (XIII) may be prepared by conventional procedures.
14) The compounds of the formula (I) wherein R10 and R11, taken together, represent a group of the formula:-
Z is carbonyl, and X, Y, W, R, R1 to R9, R13 and R14 are as previously defined for a compound of the formula (I), can be prepared by intramolecular cyclisation of a compound of the formula:-
or a base salt thereof, wherein X, Y, W, R, R1 to R9, R13 and R14 are as previously defined for this method and Z8 is a suitable leaving group, e.g. halo (preferably chloro or bromo), C1-C4 alkoxy (e.g.
methoxy or ethoxy) or benzyloxy. Where a base salt of a compound of the formula (XIV) is not used, the reaction may optionally be carried out in the presence of a suitable acid acceptor, e.g.
triethylamine.
The reaction is typically carried out in a suitable organic solvent, e.g. dichloromethane or N,N-dimethylformamide, at from room
temperature to the reflux temperature of the solvent.
The starting materials of the formula (XIV) can be prepared by conventional procedures.
15) The compounds of the formula (I) where R10 and R11, taken together, represent a group of the formula:-
and X, Y, Z, R and R1 to R9 are as previously defined for a compound of the formula (I), can be prepared by catalytic hydrogenation of a compound of the formula (I) where R10 and R11, taken together, represent a group of the formula:-
and X, Y, Z, R and R1 to R9 are as previously defined for this method.
In a typical procedure the hydrogenation is carried out in the presence of a suitable catalyst, e.g. paliadium-on-carbon, at about 345kPa (50psi) and in a suitable solvent, e.g. methanol or ethanol, at from room temperature to the reflux temperature of the solvent.
16) All the compounds of the formula (I) wherein X, Y, Z, R and R1 to R11 are as previously defined for a compound of the formula (I) may be prepared by acylation of an indole of the formula:-
wherein Y, R, R1 to R4 and R12 are as previously defined for this method, with a compound of the formula:-
The reaction may be carried out in a suitable solvent, e.g. toluene, at from room temperature to the reflux temperature.
The preferred base salts of an indole of the formula (XVI) include the alkali metal and alkaline earth metal salts, e.g. the sodium and potassium salts.
Where a compound of the formula (I) wherein R8 is -COOH is required, the product is obtained as a base salt which may be converted to the carboxylic acid by acidification in the work-up procedure.
17) The compounds of the formula (I) wherein R8 is -COOH and X, Y, Z, R, R1 to R7 and R9 to R11 are as previously defined for a compound of the formula (I) may be prepared by oxidative cleavage of a compound of the formula:-
wherein X, Y, Z, R, R1 to R7 and R9 to R11 are as previously defined for this method.
The reaction may be carried out by ozonolysis or by treatment with aqueous potassium permanganate solution.
18) The compounds of the formula (I) wherein R8 is -COOH and X, Y, Z, R, R1 to R7 and R9 to R11 are as previously defined for a compound of the formula (I) may be prepared by oxidation of a compound of the formula:-
wherein X, Y, Z, R, R1 to R7 and R9 to R11 are as previously defined for this method. A suitable oxidising agent for this purpose is chromium trioxide in pyridine.
All of the above reactions and the preparations of novel starting materials used in the preceding methods are conventional and appropriate reagents and reaction conditions for their performance or preparation as well as procedures for isolating the desired products will be well known to those skilled in the art with reference to literature precedents and the Examples and Preparations hereto.
A pharmaceutically acceptable salt of a compound of the formula (I) may be readily prepared by mixing together solutions of a compound of the formula (I) and the desired acid or base, as appropriate. The salt may precipitate from solution and be collected by filtration or may be recovered by evaporation of the solvent.
The compounds of the formula (I) are steroid 5α-reductase inhibitors and therefore they are useful in the treatment of diseases or conditions such as acne vulgaris, alopecia, seborrhoea, female hirsutism, benign prostatic
hypertrophy and male pattern baldness.
Certain compounds of the formula (I) are also useful for the treatment of human prostrate adenocarcinomas.
The compounds of the formula (I) may be tested in vitro for
testosterone 5α-reductase inhibitory activity using prostate tissue from rats or humans as follows:-
(a) The compounds of the formula (I) may be tested for their potency in inhibiting rat testosterone 5α-reductase using ventral prostate tissue from male rats, in determining inhibitory potency against rat prostatic 5α-reductase the following procedure was employed:-
Rat prostates were minced into small pieces. The tissue was homogenised in Buffer A (20mM sodium phosphate, pH 6.5, buffer containing 0.32M sucrose and 1mM dithiothreitol) with a Brinkman Polytron (Kinematica GmBH, Luzern), and then homogenised with a motor-driven (1000rpm) Potter Elvehjem (teflon-to-glass)
homogeniser. Prostate particles were obtained by centrifugation at 105,000G for 60 minutes. The pellet was washed in 4 volumes of Buffer A and recentrifuged at 105,000G. The resulting pellet was dispersed in Buffer A (1 ml per g of prostate tissue originally used) with a motor-driven Potter Elvehjem homogeniser as described above.
The particulate suspension was stored as 1 ml samples at
-70°C.
The following components, dissolved in Buffer B (40mM sodium phosphate buffer, pH 6.5), were added to a test tube: 500μl of [3H]- testosterone (IμCi, 1 nmol; Du Pont, NEN Research Products,
Stevenage, U.K.), 100μl of 0.5mM NADPH, a compound of the formula (I) dissolved in 5μl of dimethyl sulphoxide, and Buffer B to give a final reaction volume of 1ml. The mixture was warmed to 37°C and the reaction started by addition of an aliquot of prostate
paniculate suspension. The reaction mixture was incubated at 37°C for 30 minutes and then quenched by addition with vigorous mixing of 2ml of ethyl acetate containing 20μg each of testosterone and 5α- dihydrotestosterone as carriers. The aqueous and organic layers were separated by centrifugation at 2000G for 10 minutes. The organic layer was transferred to a second test tube and evaporated to dryness under nitrogen. The residue was dissolved in 50-80μl of absolute ethanol, spotted onto a silica gel 60 F254 TLC plate (E. Merck, Darmstadt, Germany) and developed in
dichloromethane:acetone (185:15).
The radiochemical content in the bands of the substrate
(testosterone) and the product (5α-dihydrotestosterone) was determined with a RITA Radio TLC Analyser (Raytest Instruments Ltd., Sheffield, U.K.). The percent of recovered radiolabel converted to 5α-dihydrotestosterone was calculated and used to determine enzyme activity. All incubations were conducted so that no more than 15% of substrate (testosterone) was converted to product.
The experimentally obtained data for a range of inhibitor
concentrations were computer fitted to a sigmoidal dose-response curve and concentrations of compound giving 50% inhibition of 5α- reductase activity (IC50's) were calculated using a SIGFIT program (De Lean, A., Munson, PJ. and Rodbard, D., American Journal of Physiology, 235, E97 (1978).
(b) The compounds of the formula (I) may be tested for their potency in inhibiting human testosterone 5α-reductase-2 using tissue from hyperplastic human prostates. In determining inhibitory potency against human prostatic 5α-reductase-2 the following procedure was employed:-
Frozen human prostate tissue was pulverised in liquid nitrogen using a steel mortar and pestle. The powdered tissue was homogenised in 4 volumes of Buffer A (20mM sodium phosphate, pH 6.5, containing 0.32M sucrose, 1mM dithiothreitol and 50μM NADPH) with an Ultra-Turrax homogeniser (Janke and Kunkel GmBH & Co., Staufen i.BR., Germany). The homogenate was centrifuged at 500G for 5 minutes to remove large particles of tissue, and the supernatant was then centrifuged at 100.000G for 1 hour. The resulting pellet was dispersed in Buffer A (1ml per g of prostate tissue originally used) with the Ultra-Turrax homogeniser. This particulate preparation was then filtered through 2 layers of cheesecloth and the filtrate was stored as 2ml samples at -70°C.
The following components, dissolved in Buffer B (25mM citrate phosphate buffer, pH 5.2), were added to a test tube: 100μl of [3H]-testosterone (1μCi, 1nmol; Du Pont, NEN Research Products,
Stevenage, U.K.), 100μl of NADPH regeneration system (5mM
NADPH, 50mM glucose 6-phosphate, 5 units/ml glucose 6-phosphate dehydrogenase), a compound of the formula (I) dissolved in 5μl of dimethyl sulphoxide, and Buffer B to give a final reaction volume of 1ml. The mixture was warmed to 37°C and the reaction started by addition of an aliquot of prostate particulate suspension. The reaction mixture was incubated at 37°C for 30 minutes and was then quenched by addition, with vigorous mixing, of 2ml of ethyl acetate containing 20μg each of testosterone and 5α-dihydrotestosterone as carriers. The aqueous and organic layers were separated by centrifugation at 2000G for 10 minutes. The organic layer was transferred to a second test tube and evaporated to dryness under nitrogen. The residue was dissolved in 50-80μl of absolute ethanol, spotted onto a silica gel 60 F254 TLC plate (E. Merck, Darmstadt, Germany) and developed in dichloromethane:acetone (185:15).
The radiochemical content in the bands of the substrate
(testosterone) and the product (5α-dihydrotestosterone) was determined with a RITA Radio TLC Analyser (Raytest Instruments Ltd., Sheffield, U.K.). The percent of recovered radiolabel converted to 5α-dihydrotestosterone was calculated and used to determine enzyme activity. All incubations were conducted so that no more than
15% of substrate (testosterone) was converted to product.
The experimentally obtained data for a range of inhibitor
concentrations was computer fitted to a sigmoidal dose-response curve and concentrations of compound giving 50% inhibition of 5α- reductase activity (IC50's) were calculated using a SIGFIT program (De Lean, A., Munson, P.J. and Rodbard, D., American Journal of Physiology, 235, E97 (1978)). (c) The compounds of the formula (I) may be tested for potency in
inhibiting steroid 5α-reductase activity in human prostate
adenocarcinomas using cell lines DU145 and HPC36M. In
determining inhibitory potency against 5α-reductase the following procedure was employed:- Human prostate adenocarcinoma cell lines were grown in Dulbecco's
Modified Eagles medium (DMEM) containing 5% serum. The cells were recovered from the medium by centrifugation, washed in serum- free DMEM and suspended at 5-10 × 106 cells/ml. in serum-free medium.
The following components were added to a test tube: 10μl of [3H]- testosterone (1μCi, 20 pmol) dissolved in ethanol (Du Pont, NEN Research Products, Stevenage, U.K.) and 5μl of an ethanol solution of a compound of the formula (I). The ethanol was evaporated under nitrogen and the testosterone and the compound were redissolved in
0.25ml of serum-free medium containing 0.25μmol NADPH. The mixture was warmed to 37°C and the reaction started by addition of 0.25ml of cell suspension (1.2-2.5 × 106 cells). The reaction mixture was incubated at 37°C for 2 hours and then quenched by addition, with vigorous mixing, of 1.5ml of ethyl acetate containing 20μg each of testosterone and 5α-dihydrotestosterone as carriers.
The aqueous and organic layers were separated by centrifugation at 2000G for 10 minutes. The organic layer, containing testosterone and its metabolites, was transferred to a second test tube and evaporated to dryness under nitrogen. The residue was dissolved in
50-80μl of absolute ethanol, spotted onto a silica gel 60 F254 TLC plate (E. Merck, Darmstadt, Germany) and developed in
dichloromethane:acetone (185: 15). The radiochemical content in the bands of the substrate
(testosterone) and the product (5α-dihydrotestosterone) was determined with a RITA Radio TLC Analyser (Raytest Instruments Ltd., Sheffield, U.K.). The percentage of recovered radiolabel converted to 5α-dihydrotestosterone was calculated and used to determine enzyme activity. All incubations were conducted so that no more than 15% of substrate (testosterone) was converted to product.
The experimentally obtained data for a range of inhibitor
concentrations was computer fitted to a sigmoidal dose-response curve and concentrations of compound giving 50% inhibition of 5α-reductase activity (IC50's) were calculated using a SIGFIT program (De Lean, A., Munson, PJ. and Rodbard D., American Journal of Physiology, 235, E97 (1978)).
(d) The compounds of the formula (I) may be tested in vitro for human testosterone 5α-reductase-1 inhibitory activity using cloned human testosterone 5α-reductase-1 according to the procedure described in Proc. Natl. Acad. Sci. USA, 87, 3640 (1990).
For human use, the compounds of the formula (I) can be
administered alone, but will generally be administered in admixture with a pharmaceutical carrier selected with regard to the intended route of administration and standard pharmaceutical practice. For example, they can be administered orally in the form of tablets containing such excipients as starch or lactose, or in the form of capsules or ovules either alone or in admixture with excipients, or in the form of elixirs, solutions or suspensions containing flavouring or colouring agents. They can be injected parenterally, for example, intravenously, intramuscularly or subcutaneously. For parenteral administration, they are best used in the form of a sterile aqueous solution which may contain other substances, for example, enough salts or glucose to make the solution isotonic with blood. For oral and parenteral administration to human patients, the daily dosage level of the compounds of the formula (I) will be from 0.01 to 20 mg/kg (in single or divided doses) and preferably will be from 0.1 to 10mg/kg except for the treatment of human prostate
adenocarcinomas where doses of up to 20mg/kg may be used. Thus tablets or capsules of the compounds will contain from 5mg to 0.5g of active compound for administration singly or two or more at a time, as appropriate. The physician in any event will determine the actual dosage which will be most suitable for an individual patient and it will vary with the age, weight and response of the particular patient. The above dosages are exemplary of the average case; there can, of
course, be individual instances where higher or lower dosage ranges are merited, and such are within the scope of this invention.
Alternatively, the compounds of the formula (I) can be administered in the form of a suppository or pessary, or they may be applied topically in the form of a lotion, solution, cream, ointment or dusting powder. For example, they can be incorporated into a cream consisting of an aqueous emulsion of polyethylene glycols or liquid paraffin; or they can be incorporated, at a concentration of between 1 and 10%, into an ointment consisting of a white wax or white soft paraffin base together with such stabilizers and
preservatives as may be required.
The compounds of the formula (I) may also be administered together with an α-antagonist (e.g. prazosin or doxazosin), an antiandrogen (e.g. flutamide) or an aromatase inhibitor (e.g. atamestane), particularly for the treatment of benign prostatic hypertrophy.
It is to be appreciated that reference to treatment includes prophylaxis as well as the alievation of established symptoms of the disease. Thus the invention further provides:- i) a pharmaceutical composition comprising a compound of the formula (I), or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable diluent or carrier; ii) a compound of the formula (I), or a pharmaceutically
acceptable salt or composition thereof, for use as a medicament;
iii) the use of a compound of the formula (I), or of a
pharmaceutically acceptable salt or composition thereof, for the manufacture of a medicament for inhibiting a steroid 5α- reductase;
iv) the use of a compound of the formula (I), or of a
pharmaceutically acceptable salt or composition thereof, for the manufacture of a medicament for the treatment of acne vulgaris, alopecia, seborrhoea, female hirsutism, benign prostatic hypertrophy, male pattern baldness or a human prostate adenocarcinoma;
v) a method of treatment of a human to inhibit a steroid 5α- reductase which comprises treating said human with an effective amount of a compound of the formula (I) or with a pharmaceutically acceptable salt or composition thereof;
vi) a method of treatment of a human to treat acne vulgaris,
alopecia, seborrhoea, female hirsutism, benign prostatic hypertrophy, male pattern baldness or a human prostate adenocarcinoma which comprises treating said human with an effective amount of a compound of the formula (I) or with a pharmaceutically acceptable salt or composition thereof; and vii) intermediates of the formulae (II), (III), (IV), (V), (VI), (VII),
(VIII), (IX) or a base salt thereof, (X) or a base salt thereof, (XI) or a base salt thereof, (XII), (XIV) or a base salt thereof, (XVIII) and (XIX).
The following Examples illustrate the preparation of the compounds of the formula (I):-
EXAMPLE 1
4-[3-([4-(1-[4-n-Propylphenyl]hex-1-yl)-1 ,4-benzoxazin- 3(2H)-on-7-yl]methylcarbonyl)indol-1-yl]butanoic acid
A solution of ethyl 4-[3-([4-(1-[4-n-propylphenyl]hex-1-yl)-1,4-benzoxazin¬3(2H)-on-7-yl]methylcarbonyl)indol-1-yl]butanoate (see Example 12)
(178mg) in 1,4-dioxane (5ml) and water (2ml) was treated with 2N aqueous sodium hydroxide solution (0.71ml) and then stirred at 20°C for 2 hours. The solution was acidified to pH1 with 2N aqueous hydrochloric acid solution, extracted with ethyl acetate and the organic phase dried with magnesium sulphate. The filtrate was concentrated under reduced pressure to provide a yellow oil that was purified by flash chromatography (silica, eluant = 3:97 methanol.dichloromethane) to give, after combination and evaporation of the relevant fractions, the title compound as a yellow foam (51mg). LRMS m/z = 595(m+1)+. Found: C, 73.84; H, 7.28; N, 4.44.
C37H42N2O5. 0.5 H2O requires C, 73.61; H, 7.18; N, 4.64%.
1H-NMR (CDCl3): δ= 0.80 (t,3H), 0.90 (t,3H), 1.20-1.40 (m,6H), 1.60 (m,2H), 2.15-2.25 (m,4H), 2.40 (t,2H), 2.60 (t,2H), 4.00 (s,2H), 4.30 (t,2H), 4.55-4.75 (AB.2H), 6.10 (t,1H), 6.75 (s,2H), 7.00 (s,1H), 7.15 (d,2H), 7.20-7.40 (m,5H), 7.80 (s,1H), 8.40 (d,1H) ppm.
EXAMPLES 2 to 11
The compounds of the following tabulated Examples of the general formula:-
were prepared by hydrolysis of the corresponding ethyl esters (see
Examples 13 to 21) using similar methods to that used in Example 1.
EXAMPLE 12
Ethyl 4-[3-([4-(1-[4-n-propylphenyl]hex-1-yl)-1 ,4-benzoxazin-3(2H)-on-7-yl]methylcarbonyl)indol-1-yl)butanoate
To a stirred solution of potassium tert-butoxide (62 mg) in N,N-dimethylformamide (4 ml) under a nitrogen atmosphere and at 20°C was added ethyl 4-[3-([1 ,4-benzoxazin-3(2H)-on-7-yl]methylcarbonyl)indol-1-yljbutanoate (see Preparation 1) (200mg). After 30 minutes, 1-bromo-1-(4- n-propylphenyl)hexane (202 mg) was added and stirring was continued for 14 hours. At this stage a further portion of potassium tert-butoxide (21 mg) and 1-bromo-1-(4-n-propylphenyl)hexane (54mg) was added and stirring was continued for 3 hours. The reaction was quenched with 2N aqueous hydrochloric acid solution (40ml) and the resulting mixture extracted with ethyl acetate. The organic phase was dried with magnesium sulphate and concentrated under reduced pressure to give a yellow oil. Column chromatography (silica, eluant= 3:1 hexane : ethyl acetate) provided, after
combination and evaporation of the relevant fractions, the title compound as a yellow oil (178mg). LRMS m/z=624 (m+1)+.
1H-NMR(CDCI3): δ= 0.85 (t,3H), 0.90 (t,3H), 1.25 (t,3H), 1.25-1.35 (m,4H), 1.60-1.70 (m,4H), 2.15-2.25 (m,4H), 2.30 (t,2H), 2.60 (t,2H), 4.00 (s,2H), 4.15 (q,2H), 4.70 (t,2H), 4.55-4.75 (AB.2H), 6.15 (t,1H), 6.75 (s,2H), 7.00 (s,1H), 7.15 (d,2H), 7.25-7.40 (m,5H), 7.80 (s,1H), 8.35 (d,1H) ppm.
EXAMPLES 13 to 20
The compounds of the following tabulated Examples of the general formula:-
were prepared by alkylation of the corresponding benzoxazinone starting materials (see Preparations 1 and 2) with the corresponding alkyl bromides by similar methods to that used in Example 12. The alkyl bromides used as starting materials were prepared by conventional methods.
Ethyl 4-[3-([1-(1-[4-isobutylphenyl]ethyl)-3,4-dihydroquinolin-2(1H)-on-6-yl]carbonyl)indol-1-yl]butanoate
3-([1-(1-[4-lsobutylphenyl]ethyl)-3,4-dihydroquinolin-2(1H)-on-6-yl]carbonyl)indole (see Preparation 5) (197mg) was dissolved in N,N-dimethylformamide (15ml) and sodium hydride (17.6mg of a 60% w/w dispersion of sodium hydride in mineral oil) was added with stirring. After 30 minutes, ethyl 4-bromobutanoate (94mg) was added and the reaction mixture was stirred at room temperature for 3 hours. 1N aqueous hydrochloric acid solution and ethyl acetate were added and the organic layer was separated and washed with water. The organic layer was then dried (magnesium sulphate) and concentrated under reduced pressure
to give a yellow oil. Flash chromatography (silica, eluant = 3:7 ethyl acetate : hexane) provided, after combination and evaporation of the relevant fractions, the title compound as a yellow oil (180mg). LRMS m/z=565 (m+1)+.
1H-NMR (CDCI3): δ= 0.85 (d,6H), 1.20 (t,3H), 1.80 (d,3H), 1.80-1.85 (m,1H), 2.10-2.20 (m,2H), 2.20-2.35 (m,2H), 2.45 (d,3H), 2.75-2.85 (m,2H), 2.85- 3.05 (m,2H), 4.05 (q,2H), 4.20 (t,2H), 6.40 (q,1H), 6.80 (d,1H), 7.10 (d,2H), 7.20 (d,2H), 7.20-7.80 (m,4H), 7.85 (s,1H), 8.40 (d,1H) ppm.
A portion (about 200mg) of the above racemic mixture was resolved into its component enantiomers by HPLC using a Chiralpak (trade mark) AD semipreparative HPLC column and eluting with 9:1 hexane: ethanol at a flow rate of 12 ml min-1.
The initially eluted product-containing fractions were combined and concentrated under reduced pressure to provide the title compound, enantiomer A (70 mg).
Analytical HPLC: Chiralpak (trade mark) AD column, eluant= 9:1
hexane:ethanol at a flow rate of 1 ml min-1, RT= 29 min (100%ee). 1 H-NMR (CDCI3): identical to that of the above racemate.
The later eluted product-containing fractions were combined and
concentrated under reduced pressure to provide the title compound, enantiomer B (56 mg).
Analytical HPLC: Chiralpak (trade mark) AD column, eluant=9:1
hexane:ethanol at a flow rate of 1 ml min-1, RT=36 min (98%ee).
1 H-NMR (CDCI3) : identical to that of the above racemate.
The following Preparations illustrate the preparation of certain intermediates used in the preceding Examples.
PREPARATION 1
Ethyl 4-[3-([1 ,4-benzoxazin-3(2H)-on-7-yl]methylcaroonyl)indol-1-yl]butanoate
Pyridine (2.2 g) was added to a stirred solution of indole (2.2 g) in toluene (100 ml) at 0°C under a nitrogen atmosphere. Methylmagnesium iodide (6.7 ml of a 30M solution in diethyl ether) was then added dropwise and the solution was cooed to -78°C. 3-Benzyloxy-4-nitrophenylacetyl chloride (see Preparation 3) (9.3mmol) was added slowly maintaining the temperature at below -60°C. The mixture was warmed to 0°C over half an hour and quenched with aqueous ammonium chloride solution. Ethyl acetate was added and the organic layer was separated and washed with aqueous ammonium chloride solution (3 × 200 ml), followed by brine (2 × 100 ml). The organic layer was dried with magnesium sulphate and concentrated under reduced pressure to give a red oil. Flash chromatography (silica, eluant=3:97 methanol : dichloromethane) gave, after combination and evaporation of the relevant fractions, the title compound as a buff solid (1.1 g). LRMS m/z=387 (m+1)+.
1H-NMR (d6-DMSO): δ= 4.20 (s,2H), 5.20 (s,2H), 6.95 (d,1H), 7.10 (s,1H), 7.15-7.35 (m,9H), 7.80 (d,1H), 7.85 (d,1H), 8.35 (d,1H) ppm.
(ii) Ethyl 4-[3-(3-benzyloxy-4-nitrophenylacetyl)indol-1-yl]butanoate
Ethyl 4-bromobutanoate (6.07 g) and potassium carbonate (4.43 g) were added to a stirred solution of the compound of Preparation 1 (i) (3.0 g) in 2-butanone (200 ml) at room temperature under a nitrogen atmosphere. The mixture was heated under reflux for 6 hours and then cooled to room temperature. The mixture was diluted with ethyl acetate and washed with 2N aqueous hydrochloric acid solution (3 × 50 ml), followed by brine (100 ml). The organic layer was dried with magnesium sulphate and
concentrated under reduced pressure to give an orange oil. This oil was purified by flash chromatography (silica, eluant= 1 :3 ethyl acetate : hexane) to provide, after combination and evaporation of the appropriate fractions, the title compound as a brown oil (2.9 g). LRMS m/z=501.7 (m+1)+.
1H-NMR (CDCI3): δ= 1.25 (t,3H), 2.15 (m,2H), 2.50 (t,2H), 4.10 (s,2H), 4.15
(q,2H), 4.25 (t,2H), 5.20 (s,2H), 6.80-7.40 (m,9H), 7.70-7.80 (m,2H), 8.40 (d,2H) ppm.
(iii) Ethyl 4-[3-(4-amino-3-hydroxyphenylacetyl)indol-1-yl]butanoate
Ammonium formate (1.78 g), 10% w/w palladium-on-carbon (300 mg) and concentrated hydrochloric acid (0.99 ml) were added to a stirred solution of the compound of Preparation 1 (ii) (2g) in ethanol (100 ml) and water (1.2 ml). The mixture was heated under reflux for 1 hour and then cooled. The slurry was filtered through a cellulose-based filter aid and the ethanol was removed under reduced pressure. The residue was partitioned between saturated aqueous sodium bicarbonate solution and ethyl acetate, the layers separated and the aqueous layer further extracted with ethyl acetate (3×20 ml). The combined organic layers were dried with magnesium sulphate and concentrated under reduced pressure to give a brown oil. This was purified by flash chromatography (silica, eluant=3:97 methanol : dichloromethane) to give, after combination and evaporation of the appropriate fractions, the title compound as a yellow solid (600 mg). LRMS m/z=381 (m+1)+.
1H-NMR (CDCI3): δ= 1.20 (t,3H), 2.15-2.25 (m,2H), 2.35 (t,2H), 4.00 (s,2H), 4.20 (q,2H), 4.30 (t,2H), 6.65-6.85 (m,2H), 7.30-7.50 (m,4H), 7.80 (s,1H),
8.40 (d,1H) ppm.
(iv) Ethyl 4-[3-(4-chloroacetylamino-3-hydroxyphenylacetyl)indol-1- yl]butanoate
OhIoroacetyl chloride (198 mg) and sodium acetate (260 mg) were added to a stirred solution of the compound of Preparation 1(iii) (600mg) in acetone (30 ml) and water (30 ml). After 3 hours the solution was acidified to pH4 using 2M aqueous hydrochloric acid solution and extracted with ethyl acetate (3 × 50 ml). The combined organic extracts were dried with magnesium sulphate and concentrated under reduced pressure to give a brown oil which was purified by flash chromatography (silica, eluant=3:97 methanol : dichloromethane) to provide, after combination and evaporation of the appropriate fractions, the title compound as a grey foam (550 mg).
LRMS m/z=421 (m-35)+.
1H-NMR (CDCI3): δ= 1.30 (t,3H), 2.25-2.35 (m,2H), 2.35 (t,2H), 4.10 (s,2H), 4.15 (q,2H), 4.20 (t,2H), 6.85 (d,1H), 6.90 (s,1H), 7.20-7.40 (m,4H), 7.60 (d,1H), 7.80 (s,1H), 8.10 (s,1H), 8.40 (d,1H), 8.60 (s,1H) ppm.
(v) Ethyl 4-[3-([1,4-benzoxazin-3(2H)-on-7-yl]methylcarbonyl)indol-1-yl]butanoate
Sodium hydride (18.6 mg of an 80% w/w dispersion in mineral oil) was added to a solution of the compound of Preparation 1 (iv) (550mg) in tetrahydrofuran (50 ml) at 0°C under an atmosphere of nitrogen. After 14 hours the reaction mixture was quenched and diluted with ethyl acetate, then washed with 1N aqueous hydrochloric acid solution (3 × 30 ml). The organic layer was dried with magnesium sulphate and concentrated under reduced pressure to give the title compound a grey solid (500 mg). LRMS m/z= 421.5 (m+1)+.
1H-NMR (CDCI3): δ= 1.25 (t,3H), 2.20 (m,2H), 2.30 (t,2H), 4.10 (s,2H), 4.15 (q,2H), 4.25 (t,2H), 4.55 (s,2H), 6.70 (d,1H), 6.90-7.00 (m,2H), 7.20-7.40 (m,3H), 7.70 (s,1H), 7.80 (s,1H), 8.40 (d,1H) ppm.
PREPARATION 2
Ethyl 4-[3-([1 ,4-benzoxazin-3(2H)-on-7-yl]carbonyl)indol-1-yl]butanoate
(i) 3-(3-Benzyloxy-4-nitrobenzoyl)indole
The title compound was prepared by a similar method to that of Preparation 1 (i) using indole and 3-benzyloxy-4-nitrobenzoyl chloride (see Preparation 4) as the starting materials. LRMS m/z=373.4(m+1)+ 1H-NMR (CDCI3): δ= 5.30 (s,2H), 7.25-7.50 (m,11H), 7.90 (d,1H), 8.40
(d,1H), 8.60 (s,1H) ppm.
(ii) Ethyl 4-[3-(3-benzyloxy-4-nitrobenzoyl)indol-1-yl)butanoate
The title compound was prepared by a similar method to that of Preparation 1(ii) using the compound of Preparation 2(i) and ethyl 4-bromobutanoate as the starting materials. LRMS m/z=487 (m+1)+
1H-NMR (CDCI3): δ= 1.20 (t,3H), 2.10-2.20 (m,2H), 2.30 (t,2H), 4.10 (q,2H), 4.20 (t,2H), 5.25 (s,2H), 7.30-7.45 (m,9H), 7.60 (s,1H), 7.95 (s,1H), 8.40 (d,2H) ppm.
(iii) Ethyl 4-[3-(4-amino-3-hydroxybenzoyl)indol-1-yl]butanoate
The title compound was prepared by a similar method to that of Preparation 1 (iii) using the compound of Preparation 2(ii) as the starting material.
LRMS m/z=367 (m+1)+
1H-NMR (CDCI3): δ= 1.20 (t,3H), 2.20 (m,2H), 2.30 (t,2H), 4.10 (q,2H), 4.20 (S.1H), 4.20 (t,2H), 6.70 (d,1H), 7.10 (s,1H), 7.20-7.40 (m,4H), 7.60 (d,2H), 8.40 (d,1H) ppm.
(iv) Ethyl 4-[3-(4-chloroacetylamino-3-hydroxybenzoyl)indol-1-yl]butanoate
The title compound was prepared by a similar method to that of Preparation 1 (iv) using the compound of Preparation 2(iii) as the starting material.
LRMS m/z=443 (m+1)+.
1H-NMR (CDCI3): δ= 1.20 (t,3H), 2.20 (m,2H), 2.35 (t,2H), 4.15 (q,2H), 4.25 (s,2H), 4.30 (t,2H), 7.30-7.45 (m,3H), 7.60 (s,2H), 7.95 (d,1H), 8.35 (s,1H), 8.45 (d,1H), 8.90 (s,1H) ppm. (v) Ethyl 4-[3-([1,4-benzoxazin-3(2H)-on-7-yl]carbonyl)indol-1-yl]butanoate
The title compound was prepared by a similar method to that of Preparation 1 (v) using the compound of Preparation 2(iv) as the starting material.
LRMS m/z=407 (m+1)+.
1H-NMR (CDCI3) : δ= 1.20 (t,3H), 2.25 (m,2H), 2.35 (t,2H), 4.10 (q,2H), 4.30 (t,2H), 4.70 (s,2H), 6.95 (d,1H), 7.30-7.50 (m,4H), 7.55 (s,1H), 8.40 (d,1H), 9.00 (s,1H) ppm.
PREPARATION 3
3-Benzyloxy-4-nitrophenylacetyl chloride
(i) Benzyl 3-benzyloxy-4-nitrobenzoate
Benzyl bromide (77 g) was added to a solution of 3-hydroxy-4-nitrobenzoic acid (40 g) and anhydrous potassium carbonate (101.1g) in N,N-dimethylformamide (450 ml) at 0°C under a nitrogen atmosphere. The mixture was heated at 60°C for 14 hours. After cooling to room
temperature, the mixture was diluted with water (1 L) and the aqueous solution extracted with ethyl acetate (3 × 300 ml). The combined organic layers were washed with brine, dried with magnesium sulphate and concentrated under reduced pressure to give a buff solid. Trituration with diethyl ether and hexane gave the title compound as a yellow solid (60.9 g). LRMS m/z=381 (m+18)+. Found: C, 69.31; H, 4.62; N, 3.83. C21H17NO5 requires C, 69.41 ; H, 4.72, N, 3.85%.
1H-NMR (CDCI3): δ= 5.25 (s,2H), 5.40 (s,2H), 7.20-7.45 (m,9H), 7.70 (d,1H),
7.85 (m,3H) ppm.
(ii) 3-Benzyloxy-4-nitrobenzyl alcohol
To an ice-cooled suspension of the compound of Preparation 3(i) (60g) and methanol (10.1 ml) in diethyl ether (1 L) under a nitrogen atmosphere was added a solution of lithium borohydride (124 ml of a 2M solution in tetrahydrofuran) dropwise. The mixture was heated under reflux for 2 hours and then cooled to room temperature. The mixture was quenched by the dropwise addition of 2N aqueous hydrochloric acid solution (400 ml) and stirred at room temperature for 24 hours. The layers were separated and the organic layer was washed with 2N aqueous hydrochloric acid solution (2 × 100 ml) followed by brine (1×200ml), then dried with magnesium sulphate
and concentrated under reduced pressure to give the title compound as a yellow solid (61 g). LRMS m/z=277 (m+18)+.
1H-NMR (CDCI3): δ= 4.75 (s,1H), 4.80 (s,1H), 5.25 (s,2H), 7.00 (d,1H), 7.20-7.50 (m,5H), 7.90 (d,1H) ppm.
(iii) 3-Benzyloxy-4-nitrobenzyl chloride
To a stirred solution of the compound of Preparation 3(ii) (19.8 g) and triethylamine (11.6 g) in tetrahydrofuran (500 ml) at 0°C under a nitrogen atmosphere was added methanesulphonyl chloride (47g). The resulting suspension was warmed to 20°C and stirred for 30 minutes. The mixture was then cooled to 0°C and tetra-n-butylammonium chloride (31.8g) was added. After 14 hours the mixture was treated with ethyl acetate and washed with aqueous sodium bicarbonate solution (3 × 200 ml) followed by 2N aqueous hydrochloric acid solution (3 × 100 ml). The organic layer was dried with magnesium sulphate and concentrated under reduced pressure to give the title compound as a yellow oil (21.3g). LRMS m/z=295 (m+18)+.
1H-NMR(CDCI3): δ= 4.55 (s,2H), 5.25 (s,2H), 7.05 (d,1H), 7.20 (s,1H), 7.20-7.50 (m,6H), 7.85 (d,1H) ppm.
(iv) Methyl 3-benzyloxy-4-nitrophenylacetate
A solution of the compound of Preparation 3(iii)(5.95 g), tetrakis- (triphenylphosphine)palladium(O) (600 mg) and diisopropylethylamine (2.98 g) in degassed methanol (150 ml) in a high pressure bomb was stirred at
110°C under an atmosphere of carbon monoxide at 345 kPa (50psi) for 4 hours. The mixture was cooled to 20°C and treated with ethyl acetate (150 ml). The mixture was washed with 2N aqueous hydrochloric acid solution (3 × 30 ml) followed by brine (50ml), dried with magnesium sulphate and
concentrated under reduced pressure to an orange oil. This was purified by flash chromatography (silica, eluant= 1 :3 ethyl acetate : hexane) to provide, after combination and evaporation of the appropriate fractions, the title compound (4.9 g). LRMS m/z=319 (m+18)+. 1H-NMR (CDCI3): δ= 3.60 (s,2H), 3.70 (s,3H), 5.20 (s,2H), 6.90 (d,1H), 7.05
(s,1H), 7.15-7.50 (m,5H), 7.85 (d,1H) ppm.
(v) 3-Benzyloxy-4-nitrophenylacetic acid To a stirred solution of the compound of Preparation 3(iv) (4.8 g) in 1,4-dioxane (70 ml) and water (50 ml) at 20°C was added 2M aqueous sodium hydroxide solution (39.8 ml). The mixture was warmed to 50°C and stirred for 2 hours, then cooled to 20°C. The pH was adjusted to pH 1 with 2N aqueous hydrochloric acid solution and the resulting suspension was extracted with ethyl acetate (3×70 ml). The combined organic extracts were washed with brine (2×30 ml), dried with magnesium sulphate and
concentrated under reduced pressure to a fawn solid. Crystallisation from ethyl acetate/hexane provided the title compound as a yellow solid (3.58 g). LRMS m/z=305 (m+18)+. Found: C, 62.96; H, 4.61; N, 4.85. C15H13NO5 requires C, 62.72; H, 4.56; N, 4.88%.
1H-NMR (CDCl3): δ= 3.65 (s,2H), 5.20 (s,2H), 6.95 (d,1H), 7.05 (s,1H), 7.20-7.45 (m,5H), 7.80 (d,1H) ppm.
(vi) 3-Benzyloxy-4-nitrophenylacetyl chloride
To a stirred solution of the compound of Preparation 3(v) (2.67 g) in dichloromethane (50 ml) was added dropwise oxalyl chloride (2.5 g). N,N-Dimethylformamide (0.5 ml) was then added dropwise and this resulted in a rapid effervescence. After 1 hour the dichloromethane and excess oxalyl chloride were removed under reduced pressure to provide the title compound as an orange oil which was not purified further.
PREPARATION 4
3-Benzyloxy-4-nitrobenzoyl chloride
(i) 3-Benzyloxy-4-nitrobenzoic acid
Sodium hydroxide (206 ml of a 2M aqueous solution) was added to a stirred solution of benzyl 3-benzyloxy-4-nitrobenzoate (30 g) in 1,4-dioxane (300 ml) and the solution was heated at 50°C for 48 hours. The solution was then cooled to 0°C and acidified with 2N aqueous hydrochloric acid solution to pH1. The resulting aqueous mixture was extracted with ethylacetate (3 × 200 ml) and the combined organic extracts were dried with magnesium sulphate and concentrated under reduced pressure to give a buff solid.
Trituration with diethyl ether and hexane gave the title compound as a pale yellow solid (20.8 g). LRMS m/z=273 (m)+. Found: C, 61.16; H, 3.96; N, 4.81. C14H1 1NO5 requires C, 61.54; H, 4.06; N, 5.13%. 1H-NMR (CDCI3): δ=5.20 (s,2H), 7.25-7.45 (m,5H), 7.70 (d,1H), 7.90 (d,1H),
7.95 (s,1H) ppm.
(ii) 3-Benzyloxy-4-nitrobenzoyl chloride
To an ice-cooled suspension of the compound of Preparation 4(i) (20 g) in dichloromethane (200 ml) was added N,N-dimethylformamide (1 ml) followed by oxalyl chloride (21.5 g). The mixture was stirred at room temperature for 2.5 hours and then concentrated under reduced pressure to give the title compound as an orange solid which was not purified further.
PREPARATION 5
3-([1-(1-[4-lsobutylphenyl]ethyl)-3,4-dihydroquinolin-2(1H)-on-6- yl]carbonyl)indole
6-Bromo-3,4-dihydroquinolin-2(1H)-one (10.44g) was dissolved in N,N-dimethylformamide (50ml) and cooled to 0°C. Sodium hydride (80% w/w dispersion in oil) (2.0g) was added and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was cooled to 0°C and 1-bromo-1-(4-isobutylphenyl)ethane (11.2g) was added. After 14 hours, 1N aqueous hydrochloric acid solution and ethyl acetate were added and the organic layer was separated, washed with water and dried with magnesium sulphate to give a yellow oil. Flash chromatography (silica, eluant=3:7 ethyl acetate: hexane) gave, after combination and evaporation of the appropriate fractions, the title compound as an oil (13.3g). LRMS m/z = 386 (m)+.
1H-NMR (CDCI3):δ= 0.85 (d,6H), 1.65 (d,3H), 1.80 (m,1H), 2.40 (d,2H), 2.80-3.00 (m,4H), 6,35 (q,1H), 6.75 (d,1H), 7.10 (d,2H), 7.15
(s,1H), 7.20 (d,2H), 7.25 (s,1H) ppm.
(ii) 6-Methoxycarbonyl-1-(1-[4-isobutylphenyl]ethyl)-3,4-dihydroquinolin-2 (1H)-one
Triethylamine (12.2ml) and tetrakis(triphenylphosphine)palladium(0)
(265mg) were added to a stirred solution of the compound of Preparation 5(i) (13.30g) in methanol (130ml) and the reaction mixture was heated at 100°C under an atmosphere of carbon monoxide at 690 kPa (100psi) in a sealed vessel for 14 hours. At this stage the reaction was incomplete and so further portions of triethylamine (12.2ml) and the palladium catalyst (265mg) were added. After a further 14 hours the solvent was evaporated under reduced pressure and the residue was partitioned between aqueous sodium bicarbonate solution and ethyl acetate. The organic layer was separated and dried with magnesium sulphate, then
concentrated under reduced pressure to give a yellow oil. Flash chromatography (silica, eluant= 3:7 ethyl acetate : hexane) gave, after combination and evaporation of the appropriate fractions, the title compound as a yellow oil (10.11g). LRMS m/z = 365 (m)+. 1H-NMR (CDCI3): δ= 0.85 (d,6H), 1.75 (d,3H), 1.85 (m,1H), 2.40
(d,2H), 2.70-2.80 (m,2H), 2.85-3.00 (m,2H), 3.80 (s,3H), 6.40 (q,1H), 6.80 (d,1H), 7.05 (d,2H), 7.15 (d,2H), 7.65 (d,1H), 7.80 (s,1H) ppm.
(iii) 6-Carboxy-1-(1-[4-isobutylphenyl]ethyl)-3,4-dihydroquinolin-2(1H)-one
The compound of Preparation 5(ii) (10.11g) was dissolved in a mixture of methanol (120ml) and tetrahydrofuran (120ml) at room temperature. 2N Aqueous sodium hydroxide solution (120ml) was then added and stirring was continued for 30 minutes. The organic solvents were removed under reduced pressure and 2N aqueous hydrochloric acid solution was added until the mixture reached pH2. The solid that precipitated was filtered off and dried to give the title compound as a white solid (8.75g). LRMS m/z = 351 (m)+. 1H-NMR (CDCI3) : δ= 0.85 (d,6H), 1.75 (d,3H), 1.85 (m,1 H), 2.40
(d,2H), 2.70-2.90 (m,2H), 2.90-3.10 (m,2H), 6.40 (q,1H), 6.80 (d,1H), 7.10 (d,2H), 7.20 (d,2H), 7.70 (d,1H), 7.85 (s,1H) ppm.
(iv) 3-([1-(1-[4-lsobutylphenyl]ethyl)-3,4-dihydroquinolin-2(1H)-on-6- yl]carbonyl)indole
A stirred solution of indole (199mg) in toluene (15ml) was treated with methylmagnesium iodide (0.624ml of a 3.0M solution in diethyl ether). After stirring at room temperature for 30 minutes a solution of the compound of Preparation 5(iii) (200mg) in toluene (3ml) was added dropwise. Stirring was continued for 2 hours and then 10% aqueous ammonium chloride solution was added and the aqueous phase extracted with ethyl acetate. The organic extract was dried (magnesium sulphate) and concentrated under reduced pressure.
Flash chromatography (silica, eluant= 1:1 hexane: ethyl acetate) gave, after combination and evaporation of the appropriate fractions, the title compound (250mg). LRMS m/z = 451 (m+1)+. 1H-NMR (CDCI3) : δ= 0.85 (d,6H), 1.80 (d,3H), 1.80-1.90 (m,1H), 2.40
(d,2H), 2.75-2.80 (m,2H), 2.90-3.05 (m,2H), 6.40 (q,1H), 7.10 (d,2H), 7.20 (d,2H), 7.20-7.70 (m,7H), 8.35 (d,1H), 8.90 (s,1H) ppm.
Claims
1. A compound of the formula:-
or a pharmaceutically acceptable salt thereof,
wherein R is H or C1-C4 alkyl; R1, R2, R3, R4, R5, R6 and R7 are each independently selected from H, C1-C4 alkyl, halo(C1-C4)alkyl, C1-C4 alkoxy and halo;
R8 is -COOH, -COOR12 or tetrazol-5-yl;
R9 is C1-C12 alkyl, C4-C12 alkenyl, C4-C12 alkynyl or C4-C7 cycloalkyi, said alkyl, alkenyl, alkynyl and cycloalkyi being optionally substituted by C4-C7 cycloalkyi, halo, C1- C4 alkoxy, C1-C4 alkylamino, di(C1-C4 alkyl)amino, aryl or a heterocyclic group;
R10 and R11, taken together, represent a group of the formula:-
or -CH=CH-
where W is directly attached to the substituted phenyl ring;
R12 is a biolabile ester-forming group;
R13 and R14 are either each independently selected from H and C1-C4 alkyl or, when taken together, represent C3-C6 alkylene;
X is a direct link or C1-C6 alkylene;
Y is C1-C6 alkylene;
W is methylene, O, S, SO or SO2;
Z is methylene, -CH(C1-C4 alkyl)-, -C(C1-C4 alkyl)2-, carbonyl or thiocarbonyl;
"aryl", used in the definition of R9, means phenyl optionally substituted by C1-C6 alkyl, C1-C6 alkoxy, halo or halo(C1-C6)alkyl; and "heterocyclic group", used in the definition of R9, means a 5- or 6-membered heterocyclic group containing 1 or 2 heteroatoms each independently selected from N, O and S, said group being optionally substituted by C1-C6 alkyl, C1-C6 alkoxy, halo(C1-C6 alkyl) or halo.
2. A compound as claimed in claim 1 wherein
R, R1, R2, R3, R4, R5, R6 and R7 are each H;
R8 is -COOH or -COOR12;
R9 is C1-C12 alkyl optionally substituted by aryl;
R10 and R11, taken together, represent a group of the formula:-
where W is directly attached to the substituted phenyl ring;
R13 and R14 are each independently selected from H and C1-C4 alkyl;
X is a direct link or C1-C3 alkylene;
Y is C1-C4 alkylene;
W is methylene or O;
Z is carbonyl; and
"aryl" means phenyl optionally substituted by C1-C6 alkyl or halo.
A compound as claimed in claim 1 or 2 wherein
R9 is C1-C6 alkyl substituted by aryl;
R13 and R14 are both H;
X is a direct link or methylene; and
"aryl" means phenyl optionally substituted by ethyl, n-propyl, isobutyl or chloro.
A compound as claimed in claim 1 , 2 or 3 wherein R9 is 1-(4-isobutylphenyl)ethyl, 1-(4-n-propylphenyl)butyl, 1-(4-isobutylphenyl)butyl, 1-(4-ethylphenyl)pentyl, 1-(4-n-propylphenyl)pentyl, 1-(4-n-propylphenyl)-hexyl, diphenylmethyl or di(4-chlorophenyl)methyl;
X is methylene;
Y is propylene; and
W is O.
5. A compound as claimed in any preceeding claim wherein R12 is C1-C6 alkyl and preferably is ethyl.
6. A compound as claimed in any preceding claim wherein R9 is 1-(4- ethylphenyl)pentyl or 1-(4-n-propylphenyl)pentyl.
7. A compound as claimed in any preceding claim wherein R8 is -COOH.
8. A pharmaceutical composition comprising a compound of the formula (I), or a pharmaceutically acceptable salt thereof, as claimed in any of the preceding claims, together with a pharmaceutically acceptable diluent or carrier.
9. A compound of the formula (I), or a pharmaceutically acceptable salt or composition thereof, as claimed in any of claims 1 to 7 and 8, respectively, for use as a medicament.
10. The use of a compound of the formula (I), or of a pharmaceutically acceptable salt or composition thereof, as claimed in any of claims 1 to 7 and 8, respectively, for the manufacture of a medicament for inhibiting a steroid 5α-reductase.
11. The use of a compound of the formula (I), or of a pharmaceutically acceptable salt or composition thereof, as claimed in any of claims 1 to 7 and 8, respectively, for the manufacture of a medicament for the treatment of acne vulgaris, alopecia, seborrhoea, female hirsutism, benign prostatic hypertrophy, male pattern baldness or a human prostate adenocarcinoma.
12. A method of treatment of a human to inhibit a steroid 5α-reductase which comprises treating said human with an effective amount of a compound of the formula (I) or with a pharmaceutically acceptable salt or composition thereof as claimed in any of claims 1 to 7 and 8, respectively.
13. A method of treatment of a human to treat acne vulgaris, alopecia, seborrhoea, female hirsutism, benign prostatic hypertrophy, male pattern baldness or a human prostate adenocarcinoma, which comprises treating said human with an effective amount of a compound of the formula (I) or with a pharmaceutically acceptable salt or composition thereof as claimed in any of claims 1 to 7 and 8, respectively.
14. A compound of the formula:-
;
; ;
or a base salt thereof;
or a base salt thereof;
or a base salt thereof;
a base salt thereof;
; or
:
wherein R, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R13, R14, W, X, Y and Z are as defined for a compound of the formula (I) in claim 1 , R15 is an ester-forming group that can be cleaved to provide a compound of the formula (I) where R8 is -COOH but which is not a biolabile ester-forming group as defined for R12 in claim 1 , R16 and R17 are each independently selected from H and C1-C4 alkyl, R18 is H or C1-C4 alkyl, R19 and R20, taken together, represent ethylene optionally substituted by phenyl or C1-C4 alkyl, R21 and R22 are either each C1-C4 alkyl or when taken together represent C2-C3 alkylene optionally substituted by C1-C4 alkyl and Z1, Z5 and Z8 are leaving groups.
15. A compound of the formula (II) as claimed in claim 14 wherein R15 is an ester-forming group that can be cleaved by hydrolysis or reduction.
16. A process for the preparation of a compound of the formula:-
wherein R is H or C1-C4 alkyl;
R1, R2, R3, R4, R5, R6 and R7 are each independently selected from H, C1-C4 alkyl, halo(C1-C4)alkyl, C1-C4 alkoxy and halo;
R8 is -COOH, -COOR12 or tetrazol-5-yl;
R9 is C1-C12 alkyl, C4-C12 alkenyl, C4-C12 alkynyl or C4-C7 cycloalkyl, said alkyl, alkenyl, alkynyl and cycloalkyl being optionally substituted by C4-C7 cycloalkyi, halo, C1-C4 alkoxy, C1-C4 alkylamino, di(C1-C4 alkyl)amino, aryl or a heterocyclic group;
R10 and R11, taken together, represent a group of the formula:
or -CH=CH-
where W is directly attached to the substituted phenyl ring;
R is a biolabile ester-forming group;
R13 and R14 are either each independently selected from H and C1-C4 alkyl or, when taken together, represent C3-C6 alkylene;
X is a direct link or C1-C6 alkylene;
Y is C1-C6 alkylene;
W is methylene, O, S, SO or SO2;
Z is methylene, -CH(C1-C4 alkyl)-, -C(C1-C4 alkyl)2-, carbonyl or thiocarbonyl;
"aryl", used in the definition of R9, means phenyl optionally substituted by C1-C6 alkyl, C1-C6 alkoxy, halo or halo(C1-C6)alkyl; and "heterocyclic group", used in the definition of R9, means a 5- or 6-membered heterocyclic group containing 1 or 2 heteroatoms each independently selected from N, O and S, said group being optionally substituted by C1-C6 alkyl, C1-C6 alkoxy, halo(C1-C6 alkyl) or halo, which comprises
(a), for the preparation of a compound of the formula (I) wherein R8 is -COOH and X, Y, Z, R, R1 to R7 and R9 to R11 are as previously defined for a compound of the formula (I) in this claim, cleavage of an ester of the formula:-
wherein R15 is an ester-forming group that can be
cleaved to provide a compound of the formula (I) where R8 is -COOH and X, Y, Z, R, R1 to R7 and R9 to R11 are as defined for this method;
(b), for the preparation of a compound of the formula (I) wherein R is -COOH and X, Y, Z, R, R1 to R7 and R9 to R11 are as previously defined for a compound of the formula (I) in this claim, acidic hydrolysis of a compound of the formula:-
(d), for the preparation of a compound of the formula (I) where X, Y, Z, R and R1 to R11 are as previously defined for a compound of the formula (I) in this claim, N-alkylation of a base salt of a compound of the formula:-
(e), for the preparation of a compound of the formula (I) wherein R8 is -COOH and X, Y, Z, R, R1 to R7 and R9 to R11 are as previously defined for a compound of the formula (I) in this claim, oxidative cleavage of a compound of the formula:-
(f), for the preparation of a compound of the formula (I) wherein R8 is -COOH and X, Y, Z, R, R1 to R7 and R9 to R11 are as defined for a compound of the formula (I) in this claim, oxidation of a compound of the formula:-
wherein X, Y, Z, R, R1 to R7 and R9 to R11 are as defined for this method: any of said methods (a) to (f) being optionally followed by conversion of the product to a pharmaceutically acceptable salt thereof or, if the product is obtained in the form of a salt, optional conversion to the free acid or base thereof.
17. A process as claimed in claim 16(a) wherein R15 is an ester-forming group that can be removed by acidic or, preferably, basic hydrolysis.
18. A process as claimed in claim 16(a) or R17 wherein R15 is C1-C6 alkyl and preferably is ethyl.
19. A process as claimed in claim 16(c) wherein the base salt of a
compound of the formula (IX) is a sodium or potassium salt and Z3 is halo.
20. A process as claimed in claim 16(d) wherein the base salt of a
compound of the formula (X) is a sodium or potassium salt and Z4 is halo and preferably is bromo.
21. A process as claimed in claim 16, 19 or 20 wherein
R, R\ R2, R3, R4, R5, R6 and R7 are each H;
R8 is -COOH or -COOR12;
R9 is C1-C12 alkyl optionally substituted by aryl;
R10 and R11, taken together, represent a group of the formula:-
R13 and R14 are each independently selected from H and C1-C4 alkyl;
X is a direct link or C1-C3 alkylene;
Y is C1-C4 alkylene;
W is methylene or O;
Z is carbonyl; and
"aryl" means phenyl optionally substituted by C1-C6 alkyl or halo.
22. A process as claimed in any of claims 16 to 21 wherein
R9 is C1-C6 alkyl substituted by aryl;
R13 and R14 are both H;
X is a direct link or methylene; and
"aryl" means phenyl optionally substituted by ethyl, n-propyl, isobutyl or chloro.
23. A process as claimed in any of claims 16 to 22 wherein R9 is 1-(4- isobutylphenyl)ethyl, 1-(4-n-propylphenyl)butyl, 1-(4-isobutylphenyl)- butyl, 1-(4-ethylphenyl)pentyl, 1-(4-n-propylphenyl)pentyl, 1-(4-n- propylphenyl)hexyl, diphenylmethyl or di(4-chlorophenyl)methyl;
X is methylene;
Y is propylene; and
W is O.
24. A process as claimed in claim 16, 19, 20, 21 , 22 or 23 wherein R12 is C1-C6 alkyl and preferably is ethyl.
25. A process as claimed in any of claims 16 to 24 wherein R9 is 1-(4- ethylphenyl)pentyl or 1-(4-n-propylphenyl)pentyl.
26. A process as claimed in claim 16 or any of claims 19 to 25 wherein R8 is -COOH.
27. A process for the preparation of a pharmaceutical composition which comprises combining a compound of the formula (I), or a
pharmaceutically acceptable salt thereof, which has been prepared by a process as claimed in any of claims 16 to 26, together with a pharmaceutically acceptable diluent or carrier.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB9403516A GB9403516D0 (en) | 1994-02-24 | 1994-02-24 | Indoles |
| GB9403516.9 | 1994-02-24 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO1995023143A1 true WO1995023143A1 (en) | 1995-08-31 |
Family
ID=10750839
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/EP1995/000439 WO1995023143A1 (en) | 1994-02-24 | 1995-02-06 | Indole derivatives as testosterone-5-alpha-reductase inhibitors |
Country Status (2)
| Country | Link |
|---|---|
| GB (1) | GB9403516D0 (en) |
| WO (1) | WO1995023143A1 (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2012110768A1 (en) | 2011-02-18 | 2012-08-23 | The University Of Birmingham | Therapeutic uses of diarylalkanes such as mitotane |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1993017014A1 (en) * | 1992-02-28 | 1993-09-02 | Pfizer Limited | Indole derivatives as steroid 5 alpha-reductase inhibitors |
| WO1993016996A1 (en) * | 1992-02-25 | 1993-09-02 | Fujisawa Pharmaceutical Co., Ltd. | Indole derivatives as testosterone-5-alpha-reductase inhibitors |
-
1994
- 1994-02-24 GB GB9403516A patent/GB9403516D0/en active Pending
-
1995
- 1995-02-06 WO PCT/EP1995/000439 patent/WO1995023143A1/en active Application Filing
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1993016996A1 (en) * | 1992-02-25 | 1993-09-02 | Fujisawa Pharmaceutical Co., Ltd. | Indole derivatives as testosterone-5-alpha-reductase inhibitors |
| WO1993017014A1 (en) * | 1992-02-28 | 1993-09-02 | Pfizer Limited | Indole derivatives as steroid 5 alpha-reductase inhibitors |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2012110768A1 (en) | 2011-02-18 | 2012-08-23 | The University Of Birmingham | Therapeutic uses of diarylalkanes such as mitotane |
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| GB9403516D0 (en) | 1994-04-13 |
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