Claims
- 1. A compound of structure ##STR42## in which G.sup.6 is t-butyl, halogen or XH;
- X is oxygen or sulphur;
- G.sup.7 is hydrogen or t-butyl;
- G.sup.2 is hydroxy, protected hydroxy or nitro;
- R.sup.10 is hydrogen or C.sub.1-4 alkyl; and
- Ar' is 6-oxo-3(1H)-pyridazinyl or a protected--6-oxo-3(1H)-pyridazinyl--, with the proviso that when G.sup.6 is t-butyl, then G.sup.7 is t-butyl.
- 2. A compound of structure (V) ##STR43## in which G.sup.2 is hydroxy or protected hydroxy;
- R.sup.10 is hydrogen or C.sub.1-4 alkyl;
- Ar' is a protected group Ar; Ar is a 6-oxo-3(1H)-pyridazinyl group; and
- A.sup.- is an anion of a strong acid.
- 3. A compound of structure ##STR44## in which, ##STR45## G.sup.8 is bromo or a group G.sup.1 is protected group R.sup.1;
- R.sup.1 is --CH.sub.2 CR.sup.2 R.sup.3 NR.sup.4 R.sup.5 or YCOR.sup.6;
- R.sup.2 is hydrogen or C.sub.1-4 alkyl;
- R.sup.3 is hydrogen or --COR.sup.6;
- R.sup.4 is hydrogen or C.sub.1-4 alkyl;
- R.sup.5 is hydrogen, C.sub.1-4 alkyl or C.sub.1-4 alkanoyl;
- R.sup.6 is hydroxy, C.sub.1-4 alkoxy, or --NR.sup.4 R.sup.5;
- Y is a bond or C.sub.1-4 alkylene;
- R.sup.7 and R.sup.8 are hydrogen or halogen;
- R.sup.10 is hydrogen of C.sub.1-4 alkyl; and
- Ar' is a protected 6-oxo-3(1H)-pyridazinyl.
Parent Case Info
This is a divisional application of U.S. Ser. No. 07/168,780, filed Mar. 16, 1988, which is a divisional of U.S. Ser. No. 06/818,626, filed Jan. 14, 1986, which is now U.S. Pat. No. 4,766,121.
The present invention relates to novel chemical compounds, intermediates useful in their preparation, pharmaceutical compositions containing them and a method of producing thyromimetic effects in certain tissues except the heart.
The naturally occurring thyroid hormones, 3,5,3'-triiodo-L-thyronine (T.sub.3) and 3,5,3',5'-tetraiodo-L-thyronine (T.sub.4) are used in replacement therapy in cases of thyroid deficiency in man.
In addition, thyroid hormones and thyromimetic analogues thereof have been given to individuals with a view to treating other conditions (Burrow, G. N., "Thyroid Hormone Therapy in non-Thyroid Disorders", The Thyroid, Eds Werner, S. C. and Ingbar, S. H., 4th Edition, Harper and Row, 1978, 974). For example, T.sub.3 and T.sub.4 have been used in the treatment of obesity (Gwinup, G., and Poucher, R. Am. J. Med. Sci., 254, 416, 1976, Asher, W. L., Current Therapeutic Res. 14, 525, 1972) and T.sub.4 and certain thyromimetics have been shown to lower serum cholesterol concentrations in atherosclerotic patients (The Coronary Drug Project Research Group, JAMA, 220, 996, 1972). However, the direct cardiac effects encountered at doses greater than those used in replacement therapy have restricted the widespread use of thyroid hormones and thyromimetic analogues thereof as therapeutic agents.
The compounds of the present invention are structurally related to T.sub.3 and T.sub.4 and have been found to exhibit selective thyromimetic activity. When administered to test animals, they mimic the effects of thyroid hormones in certain tissues at doses which have little or no direct thyromimetic activity on the heart.
The present invention therefore provides, in a first aspect, a compound of structure (I) ##STR1## in which, R.sup.1 is --CH.sub.2 CR.sup.2 R.sup.3 NR.sup.4 R.sup.5 or YCOR.sup.6;
Suitably R.sup.3 is hydrogen; preferably R.sup.3 is COR.sup.6. Suitably R.sup.4 is C.sub.1-4 alkyl and R.sup.5 is hydrogen, C.sub.1-4 alkyl or C.sub.1-4 alkanoyl; preferably R.sup.4 and R.sup.5 are both hydrogen. Suitably R.sup.6 is C.sub.1-4 alkoxy or NR.sup.4 R.sup.5; preferably R.sup.6 is hydroxy.
Suitably Y is a bond. Preferably Y is C.sub.1-4 alkylene; most preferably Y is methylene, propylene or butylene.
Suitably R.sup.7 and R.sup.8 are the same or different and are each hydrogen, nitro or amino. Preferably R.sup.7 and R.sup.8 are both C.sub.1-4 alkyl; most preferably R.sup.7 and R.sup.8 are the same and are each halogen.
Suitably X is CH.sub.2. Preferably X is sulphur; most preferably X is oxygen.
Suitably R.sup.9 is a bioprecursor of a hydroxy group for example, C.sub.1-4 alkoxy, aryl C.sub.1-4 alkoxy (for example OCH.sub.2 Ph), C.sub.1-4 alkanoyloxy (for example OCOCH.sub.3), arylC.sub.1-4 alkanoyloxy (for example OCOCH.sub.2 Ph), arylsulphonyloxy (for example toluene sulphonyloxy), alkylsulphonyloxy (for example methane sulphonyloxy), or O-glucuronide; preferably R.sup.9 is hydroxy.
Suitably R.sup.10 is C.sub.1-4 alkyl; preferably R.sup.10 is hydrogen.
Suitably, Ar is a 4-hydroxyphenyl group or a 5-hydroxy-2-pyridyl group. Preferably Ar is a 6-oxo-3(1H)-pyridyl group; most preferably, Ar is a 6-oxo-3(1H)-pyridazinyl group.
C.sub.1-4 alkyl groups either alone or as part of another group, for example, C.sub.1-4 alkoxy or C.sub.1-4 alkanoyl are methyl, ethyl, propyl or butyl; preferably, methyl or ethyl.
Halogen atoms are bromine, chlorine or iodine; preferably bromine or iodine.
Compounds of structure (I) can be obtained in the form of a racemic or diastereomeric mixture or as individual isomers or mixtures thereof. For example, in compounds of structure (I) in which R.sup.2 is hydrogen and R.sup.3 is --COR.sup.6, the group R.sup.1 is an amino acid residue of structure ##STR2## compounds of structure (I) having such a group R.sup.1 can exist in the form of the D-isomer, L-isomer or DL-mixture of isomers. Suitably, such compounds of structure (I) are provided as the DL mixture of isomers; preferably they are provided as the D-isomer or L-isomer substantially free of the other isomer.
The present invention includes all isomeric forms in resolved and unresolved states of the compounds of structure (I).
Particular compounds of structure (I) include those in which R.sup.1 is a group ##STR3## R.sup.7 and R.sup.8 are both halogen, R.sup.9 is hydroxy, R.sup.10 is hydrogen and Ar is 6-oxo-3-(1H)-pyridyl or 6-oxo-3(1H)-pyridazinyl, for example:
Further examples of compounds of the present invention include:
Compounds of structure (I) in which R.sup.4 and R.sup.5 are the same or different and are each hydrogen or C.sub.1-4 alkyl can form acid addition salts with for example, hydrochloric, hydrobromic, hydroiodic, methanesulphonic, or sulphonic acids. Acid addition salts can also be formed with the group Ar when it is a nitrogen containing heterocycle. Compounds of structure (I) in which R.sup.6 and/or R.sup.9 are OH can form salts with metal ions such as alkali metals, for example sodium or potassium or alkaline earth metals for example calcium or magnesium. Further, any carboxy group present can be optionally salified. The ability to form acid addition and/or metal salts will be subject to the nature of the relevant compounds as will be readily understood by the skilled person.
In addition, it will be appreciated that under appropriate pH conditions, compounds of structure (1) in which R.sup.1 is ##STR4## may exist as zwitterions. The present invention includes all such zwitterionic forms of the compounds of structure (I). Similarly, the present invention includes compounds of structure (I) in which the group Ar is in the zwitterionic form.
The present invention also includes the compounds of structure (I) in which the group Ar is in an alternative tautomeric form. For example, where Ar is 6-oxo-3(1H) -pyridyl, the present invention includes the tautomeric form thereof, wherein Ar is (6-hydroxy-3-pyridyl) group; similarly, where Ar is 6-oxo-3(1H)-pyridazinyl, the present invention includes the tautomeric form thereof wherein Ar is a 6-hydroxy-3-pyridazinyl group.
A process for the preparation of a compound of structure (I) or a pharmaceutically acceptable salt thereof, comprises deprotection of a compound of structure (II) ##STR5## in which G.sup.1 is a protected group R.sup.1;
The term "protected group R.sup.1 " refers to a group R.sup.1 as defined for structure (I) in which any primary or secondary amine groups are in protected form, and in which any hydroxy groups are, where appropriate, in protected form. For example, suitable protected groups R.sup.1 include those of structure ##STR6## wherein R.sup.6 is hydroxy, C.sub.1-4 alkoxy or NR.sup.4 R.sup.11, R.sup.4 is hydrogen or C.sub.1-4 alkyl and R.sup.11 is C.sub.1-4 alkanoyl, trifluoroacetyl, aryl C.sub.1-4 alkanoyl, C.sub.1-4 alkoxycarbonyl, aryl C.sub.1-4 alkoxycarbonyl or phthalamido. Preferably, R.sup.4 is hydrogen, is trifluoroacetyl and R.sup.6 is methoxy. Other suitable protected groups R.sup.1 include those of structure ##STR7## wherein R.sup.4 and R.sup.11 are as hereinbefore defined and R.sup.6 is C.sub.1-4 alkoxy. Suitable protected groups R.sup.1 of structure YCOR.sup.6 include those wherein R.sup.6 is C.sub.1-4 alkoxy. Other suitable protecting groups are as described in "Amino Acids, Peptides and Proteins" Specialist Periodical Reports, Royal Society of Chemistry, 1969, and succeeding years.
Suitable protected hydroxy groups G.sup.2 include for example, C.sub.1-4 alkoxy, aryl C.sub.1-4 alkoxy (for example, OCH.sub.2 Ph), OC.sub.1-4 alkanoyl (for example OCOCH.sub.3), OC.sub.1-4 alkanoyl aryl (for example CO.sub.2 CH.sub.2 Ph), arylsulphonyloxy (for example toluene sulphonyloxy), or alkylsulphonyloxy (for example methane sulphonyloxy); preferably C.sub.1-4 alkoxy, for example methoxy. Other suitable protecting groups are described in "Protective Groups in Organic Synthesis", Greene, T. W., John Wiley & Sons, 1981, 87.
The term protected group Ar refers to a group Ar in which the oxygen function is in protected form, for example a group of structure: ##STR8## wherein G.sup.3 is C.sub.1-4 alkoxy, aryloxy, arylC.sub.1-4 alkoxy, chloro or bromo; or a group of structure, ##STR9## wherein G.sup.4 is C.sub.1-4 alkoxy, aryloxy or arylC.sub.1-4 alkoxy.
Suitably G.sup.3 is aryloxy, (for example phenoxy) or aryl C.sub.1-4 alkoxy, (for example benzyloxy). Preferably G.sup.3 is C.sub.1-4 alkoxy, (for example, methoxy), or halogen (for example, chloro or bromo).
Suitably G.sup.4 is aryl C.sub.1-4 alkoxy (for example benzyloxy), or aryloxy (for example phenoxy). Preferably G.sup.4 is C.sub.1-4 alkoxy (for example, methoxy).
Deprotection of protected groups in G.sup.1, G.sup.2 and Ar' of structure (II) can be achieved by standard methods depending on the precise nature of the protecting groups to be removed.
In general, protected hydroxy groups G.sup.2 are preferably methoxy groups which can be removed by treatment with boron tribromide in dichloromethane or hydrogen bromide in acetic acid.
In general, protected groups R.sup.1 of structure ##STR10## are those in which R.sup.4 is hydrogen, R.sup.11 is trifluoroacetyl and R.sup.6 is methoxy. Such groups R.sup.11 and R.sup.6 can be deprotected by treatment with hydrogen bromide or hydrogen chloride in acetic acid, or aqueous sodium hydroxide in ethanol.
In general, protected groups Ar are preferably those in which G.sup.3 is methoxy or halogen, for example chlorine, and G.sup.4 is methoxy. Deprotection of protected groups Ar in which G.sup.3 or G.sup.4 are methoxy to the corresponding groups Ar can be achieved by treatment with boron tribromide in dichloromethane. Deprotection of protected groups Ar in which G.sup.3 is chlorine can be achieved by treatment with sodium acetate in acetic acid.
The sequence of deprotection steps depends on the choice of protecting groups; for example,
(1) compounds of structure (II) in which G.sup.1 is a protected group R.sup.1 in which R.sup.4 is hydrogen, R.sup.11 is trifluoroacetyl and R.sup.6 is methoxy, G.sup.2 is methoxy and Ar' is a protected group Ar in which G.sup.3 or G.sup.4 is methoxy can be deprotected by treatment first with boron tribromide in dichloromethane to deprotect the protected group Ar and convert G.sup.2 to a hydroxy group, and then with hydrochloric acid in acetic acid to deprotect the protected group R.sup.1 ; and
(2) compounds of structure (II) in which G.sup.1 and G.sup.2 are as described in (1) above and Ar' is a protected group Ar in which G.sup.3 is chlorine for example 6-chloro-pyridazine, can first be treated with sodium acetate in acetic acid to deprotect the group Ar to form the corresponding 6-oxo-3(1H)-pyridazine, and then boron tribromide in dichloromethane to convert G.sup.2 to a hydroxy group, and finally sodium hydroxide to deprotect the protected group R.sup.1.
Alternative reagents, combinations of protecting groups and order or reactions will be apparent to those skilled in the art.
Alternatively, a process for the preparation of a compound of structure (I) or a pharmaceutically acceptable salt thereof comprises
(a) reaction of a compound of structure (III) ##STR11## in which R.sup.10 and Ar' are as defined for structure (II), X is oxygen or sulphur, and G.sup.2 is a protected phenolic hydroxy group with a compound of structure (IV) ##STR12## wherein G.sup.1 is CHO, CN, CH.sub.2 Hal, a group R.sup.1 or a protected group R.sup.1, R.sup.12 is halogen or hydroxy, one of R.sup.7 and R.sup.8 is nitro and the other is bromo or nitro and Hal is halogen;
(b) reaction of a compound of structure (V) ##STR13## in which G.sup.2 and R.sup.10 are as defined for structure (III), Ar' is a protected group Ar and A.sup.- is an anion of a strong acid, with a compound of structure (IVA) ##STR14## wherein G.sup.1 is as described for structure (IV) and R.sup.7 and R.sup.8 are the same or different and each may be hydrogen, halogen, C.sub.1-4 alkyl or nitro;
(c) reaction of a compound of structure (VA) ##STR15## wherein R.sup.10 and G.sup.2 are as defined for structure (III) Ar' is a protected group Ar and Hal is halogen, with a compound of structure (IVC) ##STR16## wherein Alk is C.sub.1-4 alkyl and G.sup.1 is as defined for structure (IV);
(d) reaction of a compound of structure (III) with a compound of structure (IVD) ##STR17## in which Hal is halogen, G.sup.1 is NO.sub.2 or CN and R.sup.7 and R.sup.8 are the same or different and are each hydrogen, halogen or C.sub.1-4 alkyl;
(e) reaction of a compound of structure (VI) ##STR18## in which Ar' is a protected group Ar, R.sup.10 is as defined for structure (III) and Hal is halogen, with a compound of structure (IVE) ##STR19## in which G.sup.1 is as described for structure (IV) and R.sup.7 and R.sup.8 are the same or different and each is hydrogen, halogen or C.sub.1-4 alkyl;
(f) reaction of a compound of structure (VI) with a compound of structure (IVF) ##STR20## in which R.sup.7 and R.sup.8 are the same or different and each is hydrogen or C.sub.1-4 alkyl and G.sup.1 is as defined for structure (IV);
(g) reaction of a compound of structure (VII) ##STR21## in which G.sup.1 is NO.sub.2, CHO, CN, CH.sub.2 Hal, a group R.sup.1 or a protected group R.sup.1, Hal is halogen; G.sup.2 is hydroxy, or a protected hydroxy group, R.sup.10' is CN, CHO or CO.sub.2 C.sub.1-4 alkyl and X, R.sup.7 and R.sup.8 are as described for
(h) reacting a compound of structure (X) ##STR23## in which G.sup.1 is a protected group R.sup.1 ; R.sup.7 and R.sup.8 are the same or different and are each hydrogen or halogen; X is oxygen or sulphur, R.sup.10 is hydrogen or C.sub.1-4 alkyl and Ar' is 6-oxo-3(1H)-pyridyl, 6-oxo-3(1H)-pyridazinyl or a protected group Ar, with an acid,
(i) converting a group G.sup.1 to a group R.sup.1 or protected group R.sup.1;
(ii) converting a group G.sup.2 to a hydroxy group or a protected hydroxy group;
(iii) converting a group R.sup.10' to a group R.sup.10;
(iv) converting a group R.sup.7 or R.sup.8 into another group R.sup.7 or R.sup.8;
(v) removing any protecting groups;
(vi) forming a pharmaceutically acceptable salt.
The reaction of a compound of structure (III) with a compound of structure (IV) in which R.sup.7 and R.sup.8 are both NO.sub.2 and R.sup.12 is hydroxy can be carried out in an organic solvent in the presence of an alkyl or aralkyl sulphonyl chloride, for example, methane sulphonyl chloride or toluene sulphonyl chloride. Preferably the reaction is carried out under reflux in pyridine as a solvent in the presence of methane sulphonyl chloride. The reaction of a compound of structure (III) with a compound of structure (IV) in which R.sup.12 is halogen can be carried out by heating in a suitable organic solvent for example dichloromethane or methylethyl ketone, preferably in the presence of a base, for example, potassium carbonate.
Compounds of structure (III) in which Ar' is a protected group Ar can be prepared from compounds of structure (IIIA) ##STR24## in which R is hydrogen or a protected hydroxy group susceptible to selective removal in the presence of the protected group G.sup.2, for example OCH.sub.2 Ph, Ar' is a protected group Ar, and G.sup.2 and R.sup.10 are as defined for structure (III). Suitable reaction steps include for example, where in structure (III) X is oxygen and Ar' is a protected group Ar, acylation of a compound of structure (IIIA) wherein R is OCH.sub.2 Ph followed by hydrogenolysis.
Compounds of structure (IIIA) can themselves be prepared from compounds of structure (IIIB): ##STR25## in which R is hydroxy or a protected hydroxy group susceptible to selective removal in the presence of a protected group G.sup.2, and G.sup.2 and R.sup.10 are as defined for structure (IIIA); for example, by reaction of a compound of structure (IIIB) where R is H or a protected hydroxy group, with:
(i) a 2-alkoxy-5-halo-pyridine in the presence of n-butyl lithium to give a compound of the structure (IIIA) in which Ar' is 6-alkoxy-3-pyridine;
(ii) a 5-alkoxy-2-halopyridine in the presence of n-butyl lithium to give a compound of structure (IIIA) in which Ar' is 5-alkoxy-2-pyridine; and
(iii) a 4-alkoxy phenyl magnesium bromide, to give a compound of structure (IIIA) in which Ar' is 4-alkoxyphenyl.
Compounds of structure (III) in which X is oxygen and Ar' is a 6-oxo-3(1H)-pyridazinyl group can be prepared by reduction of a compound of structure (IIIB) in which R is a protected hydroxy group, with, for example, sodium borohydride, followed by reaction with phosphorus tribromide, sodium cyanide and then a compound of structure (VIII) for example 3,6-dichloro-pyridazine to give a compound of structure (IIIC) ##STR26## in which R is a protected hydroxy group, R.sup.10 and G.sup.2 are as defined for structure (IIIA) and Ar' is 6-chloro-3-pyridazine. Acidic or basic hydrolysis of the compound of structure (IIIC) so formed with, for example, hydrochloric acid in acetic acid or, alternatively, sodium acetate in acetic acid followed by hydrochloric acid in acetic acid, and deprotection of the group R, gives a compound of structure (III) in which X is oxygen and Ar is a 6-oxo-3(1H)-pyridazinyl group.
Compounds of structure (III) in which Ar is 6-oxo -3(1H)-pyridyl can be prepared by conversion of compounds of structure (III) in which Ar is a 6-alkoxy-3-pyridyl group.
Compounds of structure (IIIB) in which R is for example OCH.sub.2 Ph can be prepared by benzylation of compounds of structure (IIIB) where R is hydroxy.
Compounds of structure (IIIB), where R is hydroxy can be prepared by standard methods, for example as described by H. Ulrich et al, J. Org. Chem., 1974, 39, 2437.
Compounds of structure (III) in which, X is sulphur can be prepared by reaction of a compound of structure (IIIA) in which R is hydrogen, with for example chlorine and lead thiocyanate or potassium thiocyanate in methanol, followed by triphenyl phosphine and aqueous acid.
Compounds of structure (IV) can be prepared by methods known in the art, for example as described in "Thyroid Hormones and Analogues. I. Synthesis, Physical Properties and Theoretical Calculations" E.C. Jorgensen, Hormonal Proteins and Peptides, Vol. VI, 1978, Academic Press, N.Y. and references cited therein.
The reaction of a compound of structure (IVA) with a compound of structure (V) can be carried out in an organic solvent in the presence of a base and a copper catalyst and, optionally in the presence of a crown ether. Suitable organic solvents include alcohols, for example methanol or ethanol, halogenated solvents for example dichloromethane or chloroform, dimethylformamide or dimethylsulphoxide. Preferably the reaction is carried out in dichloromethane as a solvent. Suitable bases include tertiary amines, for example triethylamine, and alkali metal hydrides or alkoxides, for example sodium hydride or potassium-t-butoxide. Preferably triethylamine or potassium-t-butoxide may be used as bases. Suitable copper catalysts include copper/bronze or copper I salts, for example, copper I benzoate or copper I halides. Preferably, the reaction is carried out in the presence of copper bronze. When the base is an alkali metal hydride or alkoxide, the reaction may be carried out in the presence of a crown ether. Preferably, the reaction can be carried out in the presence of 18-crown-6. The reaction is carried out preferably at ambient temperature. Hence, the reaction is preferably carried out in the presence of triethylamine or potassium-t-butoxide and copper bronze in dichloromethane as a solvent at ambient temperature, and, where the base is potassium-t-butoxide, optionally in the presence of 18-crown-6.
Suitably A.sup.- in structure (V) may be for example perchlorate, trifluoroacetate, halide or sulphate. Preferably A.sup.- is trifluoroacetate or perchlorate. The compound of structure (V) wherein A.sup.- is trifluoroacetate can be prepared by reaction of a compound of structure (IIIA) wherein R is hydrogen with iodine tris-trifluoroacetate in trifluoroacetic anhydride and trifluoroacetic acid. Treatment of the compound of structure (V) wherein A.sup.- is trifluoroacetate with aqueous sodium perchlorate affords the compound of structure (V) A.sup.- is perchlorate.
Compounds of structure (V) can be prepared from compounds of structure (IIIA) where R is hydrogen by standard methods for the preparation of iodonium salts, for example as described by G. F. Koser in "The Chemistry of Functional Groups, Supplement D., p.1265, 1983, S. Patai and Z. Rappaport, Eds, John Wiley & Sons Ltd.
The reaction between compounds of structure (VA) and (IVC) can be carried out in the presence of a copper catalyst in an organic solvent at elevated temperature and, optionally, in the presence of a base. Preferably the reaction is carried out under reflux in pyridine in the presence of potassium carbonate and copper.
For the reaction of compounds of structure (III) and (IVD) when G.sup.1 in (IVD) is nitro, the reaction can be carried out at elevated temperature in organic solvent in the presence of a base. Preferably the reaction is carried out under reflux in methyl ethyl ketone in the presence of potassium carbonate. When, in formula (IVD) G.sup.1 is cyano, the reaction can be carried out in an organic solvent at elevated temperature in the presence of a base and optionally, a copper catalyst. Preferably the reaction is carried out at a temperature of 40-50.degree. in dimethylformamide as solvent in the presence of sodium hydride as base.
The reaction between compounds of structure (VI) and (IVE) can be carried out at elevated temperature in an organic solvent in the presence of a base.
Suitable organic solvents include, for example, dimethylformamide or dimethylsulphoxide. Suitable bases include for example sodium hydride, sodium methoxide or potassium carbonate. Suitably the reaction is carried out at a temperature of 100 to 140.degree. in dimethylformamide in the presence of sodium hydride. Alternatively, the reaction can be carried out at a temperature of 90.degree. to 140.degree. in dimethylsulphoxide in the presence of sodium or potassium hydroxide using a procedure analogous to that described in Journal of Organic Chemistry, 1968, 33, 1245.
The reaction between compounds of structure (VI) and (IVF) can be carried out in the presence of a base in an organic solvent.
The reaction between compounds of structure (VII) and (VIII) or (IX) can be carried out under basic conditions in a suitable reaction solvent at temperatures between ambient and the reflux temperature of the solvent. For example suitable bases and solvents include sodium hydride in dimethylformamide, or potassium t-butoxide in dichloromethane, optionally in the presence of a crown ether. Other suitable bases and solvents will be apparent to those skilled in the art.
Compounds of structure (VII) can be prepared by procedures analogous to those known in the art, in particular using the reactions described in paragraphs (a) to (f) and (h) above.
The reaction between a compound of structure (X) and an acid is generally carried out in a solvent at elevated temperature. The acid must be capable of removing the t-butyl group, for example, a Lewis Acid such as aluminium trichloride, or hydrobromic acid. Suitably the reaction is carried out in an organic solvent, for example toluene, anisole or N,N-dimethylaniline, optionally in the presence of a co-solvent such as nitromethane. Preferably the reaction is carried out in toluene and nitromethane in the presence of aluminium trichloride; or in acetic acid in the presence of hydrobromic acid.
Compound of structure (X) are prepared from compounds of structure (XA) ##STR27## in which G.sup.1, R.sup.7, R.sup.8, R.sup.10 and Ar' are as described for structure (X) by treatment with a Lewis acid to remove the t-butyl group adjacent to the ether link. Suitable Lewis acids will be apparent to those skilled in the art and include for example aluminium trichloride or titanium tetrachloride in a suitable solvent, for example toluene.
Compounds of structure (XA) can be prepared for example by reacting a compound of structure (XI) with a and compound of structure (IVG) ##STR28## in which G.sup.1, R.sup.7, R.sup.8, R.sup.10 and Ar' are as described for compound (X). The reaction is carried out under conditions well known for the formation of diphenyl ethers, for example in an organic solvent in the presence of a suitable oxidant. Suitably the reaction is carried out in ether in the presence of manganese dioxide as an oxidant.
Alternatively, the compounds of structure (XA) can be prepared by reacting a compound of structure (XIA) ##STR29## in which R.sup.10 and Ar' are as described for structure (XI), with a compound of structure (IVG). The reaction can be carried out in an organic solvent, for example ether, in the presence of a suitable catalyst, for example copper, mercury or sodium metaperiodate.
Compound of structure (XIA) can be prepared by bromination of compounds of structure (XI) by standard methods.
The compounds of structure (IV), (IVA), (IVC), (IVD), (IVE) and (IVF) are known or can be prepared by known methods.
The compounds of structure (III), (V), (VA), (VI), (VII), (X), (XA), (XI) and (XIA) are novel and useful intermediates for the preparation of compounds of structure (I) and as such form a further aspect of the invention.
The intermediates of structure (III), (VA), (VI) and (XI) can together be represented by the structure: ##STR30## in which G.sup.6 is t-butyl, halogen or XH; X is oxygen or sulphur; G.sup.7 is hydrogen or t-butyl; G.sup.2 is hydroxy, protected hydroxy or nitro; R.sup.10 is hydrogen or C.sub.1-4 alkyl, and Ar' is 6-oxo-3(1H)-pyridyl, 6-oxo-3(1H) -pyridazinyl or a protected group Ar, with the proviso that when G.sup.6 is t-butyl, then G.sup.7 is t-butyl.
The intermediates of structure (XA) and (XIA) can together be represented by the structure ##STR31## in which, G.sup.8 is bromo or a group ##STR32##
G.sup.1 is a protected group R.sup.1; R.sup.7 and R.sup.8 are hydrogen or halogen, R.sup.10 is hydrogen or C.sub.1-4 alkyl and Ar' is a protected group Ar, 6-oxo-3(1H)-pyridyl or 6-oxo-3(1H)-pyridazinyl.
Compounds of structure (I) wherein X is CH.sub.2 may be prepared by methods analogous to those known in the art as described in the Jorgensen review monograph and references cited therein.
The products of reactions (a) to (h) are all compounds of structure (IIA) ##STR33## in which G.sup.1 is NO.sub.2, CHO, CN, CH.sub.2 Hal, a group R.sup.1 or a protected group R.sup.1 ; Hal is halogen;
The compounds of structure (IIA) are novel and useful intermediates and form a further aspect of the invention.
The compounds of structure (IIA) can be converted to compounds of structure (I) by standard reactions well known in the art.
Compounds of structure (IIA) in which G.sup.1 is NO.sub.2, CN, CH.sub.2 Hal or CHO, can be converted into compounds of structure (IIA) in which G.sup.1 is a protected group R.sup.1 by standard techniques as described by Harington C. R. (1948) Biochem J. 43, 434; and Roche J., Michel, R., Nunez J. and Jacquemin C. (1956) C. R. Hebd Seances Acad. Sci. 244, 1507, and ibid 245, 77-80 For example, reduction of a compound of structure (IIA), in which G.sup.1 is NO.sub.2 with SnCl.sub.2 in HCl followed by reaction with ammonium nitrite and copper I cyanide affords a compound of structure (IIA) wherein G.sup.1 is CN. Further reaction with SnCl.sub.2 in HCl affords a compound of structure (IIA) in which G is CHO. Conversion of the aldehyde group so formed to a protected group R.sup.1 may be accomplished by, for example,
(i) where X is oxygen, treatment with N-acetylglycine to give an azlactone intermediate which undergoes hydrolysis and reduction to form a compound of structure (IIA) wherein G.sup.1 is a protected group R.sup.1 of structure ##STR34## where R.sup.6 is hydroxy, R.sup.4 is hydrogen and R.sup.11 is acetyl; alternatively, alcoholyis and reduction of the intermediate azlactone gives the desired compounds of structure (IIA) wherein R.sup.6 is C.sub.1-4 alkoxy, or
(ii) treatment with sodium borohydride followed by phosphorous tribromide, to form a group CH.sub.2 Hal where Hal is bromine which may be reacted with an alkyl acetamido malonate, for example, ethyl acetamido malonate, to afford a compound of structure (IIA) wherein G.sup.1 is a protected group R.sup.1 of structure ##STR35## Deprotection using standard procedures affords the desired compounds of structure (I), wherein R.sup.4 and R.sup.5 are hydrogen and R.sup.6 is hydroxy.
Further chemical modifications to prepare protected groups R.sup.1 are described in for example, "Amino Acids, Peptides and Proteins", Specialist periodical Reports, Royal Society of Chemistry, 1969, and succeeding years; "Comprehensive Organic Chemistry", E. Haslam, Ed., Pergamon Press, 1979, 5. 187; and "General and Synthetic Methods Specialist Periodical Reports", Royal Society of Chemistry, 1978, and succeeding years.
Compounds of structure (IIA) wherein G.sup.1 is a protected group R.sup.1 of structure YCOR.sup.6 or (CH.sub.2).sub.2 NR.sup.4 R.sup.11 may be prepared from compounds of structure (IIA) wherein G.sup.1 is CHO by standard techniques.
Compounds of structure (IIA) in which G.sup.2 is nitro can be converted into compounds of structure (IIA) in which G.sup.2 is hydroxy by standard techniques. For example, by reduction of the nitro group to an amino group followed by diazotisation and hydrolysis to form the hydroxy group.
Compounds of structure (IIA) wherein R.sup.7 and R.sup.8 are both nitro, can be converted to other compounds of structure (IIA) wherein R.sup.7 and R.sup.8 are not both nitro, for example,
(i) compounds of structure (IIA) wherein one of R.sup.7 and R.sup.8 is nitro and the other is amino, can be prepared by selective reduction of a compound of structure (IIA) wherein R.sup.7 and R.sup.8 are both nitro with, for example, iron in acetic acid and acetic anhydride, followed by deprotection of the intermediate acylamino group so formed at an appropriate time; alternatively, and preferably, transfer hydrogenation using cyclohexene and palladium affords directly a compound of formula (IIA) wherein one of R.sup.7 and R.sup.8 is nitro and the other is amino.
(ii) compounds of structure (IIA) wherein R.sup.7 and R.sup.8 are both amino can suitably be prepared by chemical reduction of a compound of structure (IIA) wherein R.sup.7 and R.sup.8 are both nitro with, for example, iron in acetic acid, or with SnCl.sub.2; or, preferably, by catalytic reduction of such a compound of structure (IIA) with, for example, hydrogen in the presence of a suitable metal catalyst, for example, platinum or palladium on carbon;
(iii) compounds of structure (IIA) wherein R.sup.7 and R.sup.8 are both the same halogen atom can be prepared by diazotisation of a compound of structure (IIA) wherein R.sup.7 and R.sup.8 are both amino, with a suitable diazotising agent, for example sodium nitrite in sulphuric acid and acetic acid, followed by reaction of the intermediate bis-diazonium ion so formed with a suitable halogenating agent. For example, where, in structure (IIA) R.sup.7 and R.sup.8 are both bromine, treatment with copper I bromide and hydrogen bromide in the presence of urea. Other suitable halogenating agents depending on the nature of R.sup.7 and R.sup.8 in structure (IIA), for example treatment with potassium iodide and iodine affords a compound of formula (IIA) wherein R.sup.7 and R.sup.8 are both iodine.
(iv) compounds of structure (IIA) wherein R.sup.7 and R.sup.8 are different halogen atoms can be prepared from compounds of structure (IIA) wherein one of R.sup.7 and R.sup.8 is nitro and the other is amino. The amino group in the compound of structure (IIA) may be diazotised and then halogenated as hereinbefore described in (iii) to form a compound (IIA) wherein one of R.sup.7 and R.sup.8 is halogen and the other is nitro. Conversion of the nitro group, via reduction (to form a compound (IIA) wherein one of R.sup.7 and R.sup.8 is halogen and the other is amino), diazotisation and finally halogenation (using a different halogenating agent to that used in the first stage) affords a compound of structure (IIA) wherein R.sup.7 and R.sup.8 are different halogen atoms.
(v) compounds of structure (IIA) wherein one or both of R.sup.7 and R.sup.8 are hydrogen can be prepared by reduction of suitable diazonium or bis-diazonium salts prepared as described in (iii) and (iv).
Compounds of structure (I) wherein R.sup.4 and R.sup.5 are both hydrogen and/or R.sup.6 is hydroxy may be converted to other compounds of structure (I). For example,
(i) compounds of structure (I) wherein R.sup.4 is hydrogen or C.sub.1-4 alkyl and R.sup.5 is C.sub.1-4 alkanoyl may be prepared by acylation of a compound of structure (I) wherein R.sup.4 is hydrogen or C.sub.1-4 alkyl and R.sup.5 is hydrogen.
(ii) compounds of structure (I) wherein R.sup.6 is C.sub.1-4 alkoxy may be prepared by esterification of a compound of structure (I) wherein R.sup.6 is hydroxy.
Compounds of structure (I) wherein R.sup.6 is --NR.sup.4 R.sup.5 can be prepared by reaction of a compound of structure (I) wherein R.sup.6 is C.sub.1-4 alkoxy with ammonia or an appropriate amine.
The compounds of structure (I) exhibit biological activity which can be demonstrated in the following tests:
(i) the induction of mitochondrial .alpha.-glycerophosphate dehydrogenase (GPDH;EC 1.1.99.5). This assay is particularly useful since in certain species e.g. rats it is induced specifically by thyroid hormones and thyromimetics in a dose-related manner in responsive tissues e.g. liver, kidney and the heart (Westerfield, W. W., Richert, D. A. and Ruegamer, W. R., Endocrinology, 1965, 77, 802). The assay allows direct measurement in rats of a thyroid hormone-like effect of compounds and in particular allows measurement of the direct thyroid hormone-like effect on the heart;
(ii) the elevation of basal metabolic rate as measured by the increase in whole body oxygen consumption;
(iii) the stimulation of the rate of beating of atria isolated from animals previously dosed with thyromimetics;
(iv) the change in total plasma cholesterol levels as determined using a cholesterol oxidase kit (for example, the Merck CHOD iodide colourimetric kit)
(v) the measurement of LDL (low density lipoprotein) and HDL (high density lipoprotein) cholesterol in lipoprotein fractions separated by ultracentrifugation; and
(vi) the change in total plasma triglyceride levels as determined using enzymatic colour tests, for example the Merck System GPO-PAP method.
The compounds of structure (I) have been found to exhibit selective thyromimetic activity in these tests,
(a) by increasing the metabolic rate of test animals, and raising hepatic GPDH levels at doses which do not significantly modify cardiac GPDH levels, and
(b) by lowering plasma cholesterol and triglyceride levels, and the ratio of LDL to HDL cholesterol at doses which do not significantly modify cardiac GPDH levels.
The compounds of structure (I) may therefore be used in therapy, in the treatment of conditions which can be alleviated by compounds which selectively mimic the effects of thyroid hormones in certain tissues whilst having little or no direct thyromimetic effect on the heart. For example, compounds of structure (I) which raise hepatic GPDH levels and metabolic rate at doses which do not significantly modify cardiac GPDH levels are indicated in the treatment of obesity.
Compounds of structure (I) which lower total plasma cholesterol, the ratio of LDL-cholesterol to HDL-cholesterol and triglyceride levels at doses which do not significantly modify cardiac GPDH levels are indicated for use as general antihyperlipidaemic (antihyperlipoproteinaemic) agents i.e. in the treatment of patients having elevated plasma lipid (cholesterol and triglyceride) levels. In addition, in view of this effect on plasma cholesterol and triglyceride, they are also indicated for use as specific anti-hypercholesterolaemic and antihypertriglyceridaemic agents.
Patients having elevated plasma lipid levels are considered at risk of developing coronary heart disease or other manifestations of atherosclerosis as a result of their high plasma cholesterol and/or triglyceride concentrations. Further, since LDL-cholesterol is believed to be the lipoprotein which induces atherosclerosis, and HDL-cholesterol believed to transport cholesterol from blood vessel walls to the liver and to prevent the build up of atherosclerotic plaque, anti-hyperlipidaemic agents which lower the ratio of LDL-cholesterol to HDL cholesterol are indicated as anti-atherosclerotic agents.
The present invention also provides a method of producing selective thyromimetic activity in certain tissues except the heart which comprises administering to an animal in need thereof an effective amount to produce said activity of a compound of structure (I) or a pharmaceutically acceptable salt thereof.
The present invention also relates to a method of lowering plasma lipid levels and a method of lowering the ratio of LDL-cholesterol to HDL-cholesterol levels by suitably administering a compound of this invention or a pharmaceutically acceptable salt thereof.
In addition, compounds of structure (I) may be indicated in thyroid hormone replacement therapy in patients with compromised cardiac function.
In therapeutic use the compounds of the present invention are usually administered in a standard pharmaceutical composition.
The present invention therefore provides in a further aspect pharmaceutical compositions comprising a compound of structure (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. Such compositions include those suitable for oral, parenteral or rectal administration.
Compounds of structure (I) and their pharmaceutically acceptable salts which are active when given orally can be formulated as liquids for example syrups, suspensions or emulsions, tablets, capsules and lozenges.
A liquid composition will generally consist of a suspension or solution of the compound or pharmaceutically acceptable salt in a suitable liquid carrier(s), for example ethanol, glycerine, sorbitol, non-aqueous solvent such as polyethylene glycol, oils or water, with a suspending agent, preservative, surfactant, wetting agent, flavouring or colouring agent. Alternatively, a liquid formulation can be prepared from a reconstitutable powder.
For example a powder containing active compound, suspending agent, sucrose and a sweetener can be reconstituted with water to form a suspension; and a syrup can be prepared from a powder containing active ingredient, sucrose and a sweetener.
A composition in the form of a tablet can be prepared using any suitable pharmaceutical carrier(s) routinely used for preparing solid compositions. Examples of such carriers include magnesium stearate, starch, lactose, sucrose, microcrystalline cellulose and binders, for example polyvinylpyrrolidone. The tablet can also be provided with a colour film coating, or colour included as part of the carrier(s). In addition, active compound can be formulated in a controlled release dosage form as a tablet comprising a hydrophilic or hydrophobic matrix.
A composition in the form of a capsule can be prepared using routine encapsulation procedures, for example by incorporation of active compound and excipients into a hard gelatin capsule. Alternatively, a semi-solid matrix of active compound and high molecular weight polyethylene glycol can be prepared and filled into a hard gelatin capsule; or a solution of active compound in polyethylene glycol or a suspension in edible oil, for example liquid paraffin or fractionated coconut oil can be prepared and filled into a soft gelatin capsule.
Compound of structure (I) and their pharmaceutically acceptable salts which are active when given parenterally can be formulated for intramuscular or intravenous administration.
A typical composition for intra-muscular administration will consist of a suspension or solution of active ingredient in an oil, for example arachis oil or sesame oil. A typical composition for intravenous administration will consist of a sterile isotonic aqueous solution containing, for example active ingredient, dextrose, sodium chloride, a co-solvent, for example polyethylene glycol and, optionally, a chelating agent, for example ethylenediamine tetracetic acid and an anti-oxidant, for example, sodium metabisulphite. Alternatively, the solution can be freeze dried and then reconstituted with a suitable solvent just prior to administration.
Compounds of structure (I) and their pharmaceutically acceptable salts which are active on rectal administration can be formulated as suppositories. A typical suppository formulation will generally consist of active ingredient with a binding and/or lubricating agent such as a gelatin or cocoa butter or other low melting vegetable or synthetic wax or fat.
Compounds of structure (I) and their pharmaceutically acceptable salts which are active on topical administration can be formulated as transdermal compositions. Such compositions include, for example, a backing, active compound reservoir, a control membrane, liner and contact adhesive.
The typical daily dose of a compound of structure (I) varies according to individual needs, the condition to be treated and with the route of administration. Suitable doses are in the general range of from 0.001 to 10 mg/kg bodyweight of the recipient per day.
Within this general dosage range, doses can be chosen at which the compounds of structure (I) lower plasma cholesterol levels and raise metabolic rate with little or no direct effect on the heart. In general, but not exclusively, such doses will be in the range of from 0.5 to 10 mg/kg.
In addition, within the general dose range, doses can be chosen at which the compounds of structure (I) lower plasma cholesterol levels and have little or no effect on the heart without raising metabolic rate. In general, but not exclusively, such doses will be in the range of from 0.001 to 0.5 mg/kg.
It is to be understood that the 2 sub ranges noted above are not mutually exclusive and that the particular activity encountered at a particular dose will depend on the nature of the compound of structure (I) used.
Preferably, the compound of structure (I) is in unit dosage form, for example, a tablet or a capsule so that the patient may self-administer a single dose. In general, unit doses contain in the range of from 0.05-100 mg of a compound of structure (I). Preferred unit doses contain from 0.05 to 10 mg of a compound of structure (I).
The active ingredient may be administered from 1 to 6 times a day. Thus daily doses are in general in the range of from 0.05 to 600 mg per day. Preferably, daily doses are in the range of from 0.05 to 100 mg per day. Most preferably from 0.05 to 5 mg per day.
US Referenced Citations (4)
| Number |
Name |
Date |
Kind |
|
3149153 |
Blank et al. |
Sep 1964 |
|
|
3287396 |
Blank et al. |
Nov 1966 |
|
|
3477954 |
Reynolds et al. |
Nov 1969 |
|
|
4888423 |
Odorisio et al. |
Dec 1989 |
|
Foreign Referenced Citations (3)
| Number |
Date |
Country |
| 1200832 |
Sep 1965 |
DEX |
| 289M |
Aug 1960 |
FRX |
| 1047082 |
Nov 1966 |
GBX |
Non-Patent Literature Citations (11)
| Entry |
| Andrea, T. A. et al., "Binding of Thyroid Hormones and Analogues to the Human Plasma Protein Prealbumin," Biochemistry, vol. 19, pp. 55-63 (1980). |
| Dietrich, S. W. et al., "Thyroxine Analogues, 23 Quantitative Structure-Active Correlation Studies of In Vivo and In Vitro Thyromumetic Activities," Journal of Medicinal Chemistry, vol. 20, No. 7, pp. 863-880 (Jul. 1977). |
| Jorgensen, E. C. et al., "The Nature of the Thyroid Hormone Receptor," Int. Contr. Ser.-Excepta Med., 378, Thyroid Res., pp. 303-306 (1976). |
| Gharib, H. et al., "Radioimmunoassay for Triiodothyronine (T.sub.3): U, Affinity and Specificity of the Antibody for T.sub.3, " J. Clin. Endocrinol. Metab., vol. 33, No. 3, pp. 509-516 (Sep. 1971). |
| Ahmad, P. et al., "Parachors in Drug Design," Biochem. Pharm., vol. 24, No. 10, pp. 1103-1109 (1975). |
| Korener, D. et al., "binding of Selected Iodothyronine Analogues to Receptor Cites of Isolated rat Hepatic Nuclei," J. Biol. Chem., vol. 250, No. 16, pp. 6417-6423 (1975). |
| Goldfine, I. D. et al., "Activities of Thyroid Hormones and Related Compounds in an In Vitro Thymocyte Assay," J. Biol. Chem., vol. 251, No. 14, pp. 4233-4238 (1976). |
| Simon, Z. et al., "Studiu Structura Chimica-Activitate biologica Pentru Situsul Fixator de Tiroxina al Prealbuminei Umane," Timisoara Med., vol. 26, No. 3, pp. 26-28 (1981). |
| Gwinup, G. et al., Am. J. Med. Sci., vol. 254, pp. 416-420 (Oct. 1967). |
| Asher, N. L., Current Therapeutic res., vol. 14, No. 8, pp. 525-539 (Aug. 1972). |
| The Coronary Drug Project, Jama, vol. 220, No. 7, pp. 996-1008 (May 1972). |
Divisions (2)
|
Number |
Date |
Country |
| Parent |
168780 |
Mar 1988 |
|
| Parent |
818626 |
Jan 1986 |
|
Patent Grant
5061798
