Claims
- 1. A compound of formula (II): ##STR45## wherein: R.sup.1 is
- (a) carboxy,
- (b) C.sub.1 -C.sub.4 -alkoxycarbonyl,
- (c) --NHSO.sub.2 CF.sub.3, or ##STR46## (e) --PO(OR.sup.9)R.sup.9, (f) --PO(OR.sup.9).sub.2,
- (g) --SO.sub.2 NH-heteroaryl,
- (h) --CH.sub.2 CO.sub.2 NH-heteroaryl,
- (i) --SO.sub.2 NH--CO--R.sup.25,
- (j) --CH.sub.2 SO.sub.2 NH--CO--R.sup.25,
- (k) --CONH--SO.sub.2 R.sup.25,
- (l) --CH.sub.2 CONH--SO.sub.2 R.sup.25,
- (m) --NHSO.sub.2 NCHO--R.sup.25,
- (n) --NHCONHSO.sub.2 R.sup.25,
- (o) --SO.sub.2 NHCONHR.sup.25 ;
- R.sup.2 and R.sup.3 are independently
- (a) hydrogen,
- (b) C.sub.1 -C.sub.4 -alkyl, or
- (c) halo;
- R.sup.4 and R.sup.5 are independently
- (a) hydrogen,
- (b) C.sub.1 -C.sub.6 -alkyl,
- (c) C.sub.1 -C.sub.6 -alkoxy, or
- (d) halo;
- R.sup.6 is
- (a) C.sub.1 -C.sub.6 -alkyl,
- (b) C.sub.1 -C.sub.6 -alkenyl,
- (c) C.sub.1 -C.sub.4 -alkoxy-C.sub.1 -C.sub.6 -alkyl,
- (d) C.sub.1 -C.sub.4 -alkylthio-C.sub.1 -C.sub.6 -alkyl,
- (e) C.sub.1 -C.sub.4 -alkoxy-C.sub.1 -C.sub.6 -alkenyl, or
- (f) C.sub.1 -C.sub.4 -alkylthio-C.sub.1 -C.sub.6 -alkenyl;
- E is --S--;
- p is 0 or 1;
- X is ##STR47## (b) --S--or (c) --OCH.sub.2 --;
- q is 0 or 1;
- R.sup.14 is H;
- R.sup.15 is
- (a) H,
- (b) C.sub.1 -C.sub.6 -alkyl,
- (c) substituted C.sub.1 -C.sub.6 -alkyl wherein the substituent is selected from the group consisting of
- (i) hydroxy,
- (ii) amino,
- (iii) guanidino,
- (iv) C.sub.1 -C.sub.4 -alkylthio,
- (v) carboxy,
- (vi) carboxamido,
- (vii) C.sub.1 -C.sub.4 -alkoxycarbonyl, or ##STR48## (d) benzyl, (e) 4-hydroxybenzyl,
- (f) 3-indolylmethyl,
- (g) 4-imidazolylmethyl, or
- (h) phenyl; and
- R.sup.16 is H or C.sub.1 -C.sub.4 -alkyl
- Y is
- (a) --O--, ##STR49##
- 2. A compound of claim 1 wherein: R.sup.2, R.sup.3, R.sup.4 and R.sup.5 are hydrogen; and p and q are zero.
- 3. A compound of claim 2 wherein:
- R.sup.1 is
- (a) carboxy,
- (b) C.sub.1 -C.sub.4 -alkoxycarbonyl, ##STR50##
- 4. A compound of claim 3 wherein:
- R.sup.6 is C.sub.1 -C.sub.6 -alkyl,
- R.sup.15 and R.sup.16 are each hydrogen;
- Y is --NH--.
- 5. A compound of claim 4 selected from the group consisting of:
- (1) 2-butyl-1-(2'-carboxybiphen-4-yl)-methyl-1,4,6,7-tetrahydroimidazo[4,5-e]-[1,4]diazepine-5,8-dione; and,
- (2) 2-butyl-1-(2'-(tetrazol-5-yl)biphen-4-yl)methyl-1,4,6,7-tetrahydroimidazo[4,5-e]-[1,4]diazepine-4-methyl-5,8-dione.
- 6. A pharmaceutical composition useful in the treatment of hypertension which comprises a pharmaceutically acceptable carrier an a pharmaceutically effective amount of a compound of claim 1.
- 7. A method of treating hypertension which comprises administering to a patient in need of such treatment a pharmaceutically effective amount of a compound of claim 1.
- 8. An ophthalmalogical formulation for the treatment of ocular hypertension comprising an ophthalamologically acceptable carrier and an effective ocular antihypertensive amount of a compound of claim 1.
- 9. A method of treating ocular hypertension comprising administering to a patient in need of such treatment an effective ocular antihypertensive amount of a compound of claim 1.
BACKGROUND OF THE INVENTION
This application is a continuation-in-part of co-pending application Ser. No. 360,673 filed June 1, 1989 now abandoned.
Renin-angiotensin system (RAS) plays a central role in the regulation of normal blood pressure and seems to be critically involved in hypertension development and maintenance as well as congestive heart failure. Angiotensin II (A II), is an optapeptide hormone produced mainly in the blood during the cleavage of angiotensin I by angiotensin converting enzyme (ACE) localized on the endothelium of blood vessels of lung, kidney, and many other organs. It is the end product of the renin-angiotensin system (RAS) and is a powerful arterial vasoconstrictor that exerts its action by interacting with specific receptors present on cell membranes. One of the possible modes of controlling the RAS is angiotensin II receptor antagonism. Several peptide analogs of A II are known to inhibit the effect of this hormone by competitively blocking the receptors, but their experimental and clinical applications have been limited by partial agonist activity and lack of oral absorption [M. Antonaccio. Clin. Exp. Hypertens. A4, 27-46 (1982); D. H. P. Streeten and G. H. Anderson, Jr.--Handbook of Hypertension, Clinical Pharmacology of Antihypertensive Drugs, ed. A. E. Doyle, Vol. 5, pp. 246-271, Elsevier Science Publisher, Amsterdam, The Netherlands, 1984].
Recently, several non-peptide compounds have been described as A II antagonists. Illustrative of such compounds are those disclosed in U.S. Pat. Nos. 4,207,324; 4,340,598; 4,576,958; and 4,582,847 in European Patent Applications 028,834; 245,637; 253,310; 291,969; 323,841; 324,377 and and in articles by A. T. Chiu, et al. [Eur. J. Pharm. Exp. Therap, 13-21 (1988)] and by P. C. Wong, et al. [J. Pharm. Exp. Therap, 247, 1-7(1988)]. All of the U.S. Pat. Nos., European Patent Applications 028,834 and 253,310 and the two articles disclose substituted imidazole compounds which are generally bonded through a lower alkyl bridge to a substituted phenyl. European Patent Application 245,637 discloses derivatives of 4,5,6,7 tetrahydro 2H-imidazo[4,5c]-pyridine-6-carboxylic acid and analogs thereof as antihypertensive specifically Ca.sup.2+ channel blockers, and European Patent Application 323,841 discloses substituted pyrroles, pyrazoles and triazoles as angiotensin II antagonists.
This invention is directed to novel substituted imidazo-fused 7-member ring heterocyclic compounds of the formula (I) and to novel substituted imidazo compounds of the formula (Ia) both of which are angiotension II antagonists and are useful in the treatment of hypertension and congestive heart failure. Specifically, the compounds of this invention contain an imidazole moiety which is substituted at the 1 and 2 positions and to which a seven member heterocyclic ring is fused at the 4 and 5 positions or which is substituted at the 4 and 5 positions. Additionally, pharmaceutically acceptable compositions of these novel compounds, as the sole therapeutically active ingredient and in combination with diuretics and other antihypertensive agents, including beta-blockers, angiotensin converting enzyme inhibitors, calcium channel blockers or a combination thereof are disclosed and claimed. Further, methods of treating hypertension, congestive heart failure and elevated intraocular pressure are described and claimed.
This invention relates to compounds of the formulae (I) and (Ia): ##STR2## wherein: R.sup.1 is
Except where specifically defined to the contrary, the terms "alkyl", "alkenyl", "alkynyl", "alkoxy" and "acyl" include both straight-chain and branch-chain species of the term.
One embodiment of the instant invention is represented by the formula (II) ##STR13## wherein: R.sup.1 is
One class of this embodiment is the compounds of the formula (II) wherein R.sup.2, R.sup.3, R.sup.4 and R.sup.5 are hydrogen and p and q are 0. A sub-class of these compounds is the set of compounds wherein R.sup.1 is carboxy, C.sub.1 -C.sub.4 -alkoxycarbonyl or tetrazole. Illustrating this sub-class are the compounds wherein R.sup.6 is C.sub.1 -C.sub.6 -alkyl, R.sup.15 and R.sup.16 are hydrogen and Y is --NH--. Exemplifying this class are the following compounds.
A second embodiment of the instant invention is represented by the formula (III) ##STR18## wherein: R.sup.1 is
One class of this embodiment is the compounds of the formula (III) wherein R.sup.2, R.sup.3, R.sup.4 and R.sup.5 are hydrogen and p and q are 0. A sub-class of these compounds is the set of compounds wherein R.sup.1 is carboxy, C.sub.1 -C.sub.4 alkoxycarbonyl or tetrazole. Illustrating this sub-class are the compounds wherein R.sup.6 is C.sub.1 -C.sub.6 -alkyl, R.sup.15 and R.sup.16 are hydrogen and Y is --NH--. Exemplifying this class are the following compounds.
A third embodiment of the instant invention is represented by the formula (IV) ##STR23## wherein: R.sup.1 is
One class of this embodiment is the compounds of the formula (IV) wherein R.sup.2, R.sup.3, R.sup.4 and R.sup.5 are hydrogen and p and q are 0. A sub-class of these compounds is the set of compounds wherein R.sup.1 is carboxy, C.sub.1 -C.sub.4 -alkoxycarbonyl or tetrazole. Illustrating this sub-class are the compounds wherein R.sup.6 is C.sub.1 -C.sub.6 -and R.sup.9, R.sup.15 and R.sup.16 are hydrogen. Exemplifying this class are the following compounds.
One embodiment of the formula (Ia) compounds of the invention are those wherein R.sup.2, R.sup.3 R.sup.4 and R.sup.5 are hydrogen and p and q are o. A sub-class of these compounds are those wherein R.sup.6 is C.sub.1 -C.sub.6 -alkyl and r is 1. Exemplifying this class are the following compounds:
The compounds (I) of the present invention can be prepared from intermediates such as those of formula (1): ##STR27## wherein J and K are respectively: (a) CONR.sup.16, NHR.sup.16 ;
Intermediates (1) are converted to products (I) by cyclization of J to K by treatment with a bidentate agent in an alkylation or condensation procedure as described in detail below. This cyclization introduces the fused 7-membered ring heterocycle of formula (I).
Intermediates (1) can be prepared as shown in Scheme 1 by treatment of an alkylating agent (2) wherein L is a good leaving group such as C.sub.1, Br, I, O-mesyl or 0-tosyl and an imidazole (7) wherein J and K are independently halo, CONHR.sup.16, CO.sub.2 R.sup.7, NHR.sup.16 moieties (R7=H). The alkylation reaction of Scheme 1 is conveniently carried out in anhydrous dimethyl formamide in the presence of bases such as sodium hydride or potassium t-butoxide for a period of 1-24 hours at temperatures of 20.degree.-100.degree. C. Substituent groups on alkylating agent (2) and imidazole (7) may need to be suitably protected. Examples of such protecting groups can be found in the text by T. W. Greene, Protective Groups In Organic Synthesis, John Wiley & Sons, 1981. Chromatography on silica gel is employed to separate isomers and to remove side products which may arise from alkylation on NHR.sup.16 when this substituent is present. ##STR28##
Alkylating agent (2) may be prepared as described in EPO publications 253,210 and 291,969 and the references cited therein. A useful method to prepare the preferred alkylating agents 6a, 6b and 6c is shown in reaction Scheme 2. ##STR29## As outlined in Scheme 2, 4-bromotoluene is treated with t-BuLi followed by the addition of a ZnCl.sub.2 solution to yield an organozinc compound (3). Compound (3) is then coupled with 4a or 4b in the presence of a Ni(PPh.sub.3).sub.2 Cl.sub.2 catalyst to produce the desired biphenyl compound 5a or 5b. Similarly, 1-iodo-2-nitrobenzene (4c) is coupled with organozinc compound (3) in the presence of a Pd(PPh.sub.3).sub.4 catalyst (prepared by treating Cl.sub.2 Pd(PPh.sub.3).sub.2 with (i-Bu).sub.2 AlH (2 equiv.)) to yield the biphenyl compound (5c). Precursors 5a, 5b and 5c are converted to halomethyl derivatives 6a, 6b and 6c respectively according to procedures described in EPO publications 253,310 and 291,969.
The imidazoles (7) required in alkylation Scheme 1 can be prepared by a number of methods well known in the literature including those described in EPO publication 253,310. A useful method of generating compound (7) wherein J and K are NH.sub.2 and CONHR.sup.16 or CO.sub.2 R.sup.7 and p is zero is illustrated in Scheme 3. ##STR30##
The synthesis of intermediate (1) wherein J is NHR.sup.16 and K is CONHR.sup.16 or CO.sub.2 R.sup.7 (R.sup.7 =Ethyl) and p is zero can be accomplished by the alkylation of the cyanoamidine (13) with benzylic halide or pseudohalide (2) as outlined in Scheme 4. ##STR31## Cyanoamidine (13) is prepared according to the methods described by Edenhofer, Helv. Chim Acta, 58, 2192(1975).
Cyanoamidine (13) is alkylated employing the appropriately protected alkylating agent (2). For example, an R.sup.1 carboxyl group can be conveniently protected as a t-butyl ester and an R.sup.1 tetrazole group n N-trityl derivative The alkylated cyanomidine (14) is purified by silica gel chromatography as is the ring-closed product (15). Conversion of (15) to amide (16) can be accomplished by heating the ester with R.sup.16 NH.sub.2 in an inert solvent such as ethanol. Compound (15) can be alkylated on the amino moiety using a small excess of R.sup.16 -I in DMF in the presence of NaH.
Compounds of formula (1) wherein J and K are either C1 and CH.sub.2 OH or CH.sub.2 OH and C1 respectively are also useful intermediates the preparations of which are described in EPO publication 253,310. The primary alcohol moiety in these compounds, CH.sub.2 OH, can be oxidized directly to the corresponding --CO.sub.2 CH.sub.3 ester groups using MnO.sub.2 in the presence of NaCN and acetic acid in methanol as illustrated in Scheme 5. 43 ##STR32##
Compounds (19) and (21) from Scheme 5 can be further converted to thiol compounds as illustrated by the methodology of Scheme 6. Scheme 6 also illustrates an alternate route to amino compounds (22) which involves azide displacement of C1 followed by hydrogenation. ##STR33##
Formation of the products (I) wherein the fused ring A contains Y=NR.sup.16 is carried out from intermediates (1) wherein J and K are (NHR.sup.16, CONHR.sup.16) or (CONHR.sup.16, NHR16) respectively by treating (1) in DMF with L--C(O)--C(R.sup.14)(R.sup.15)-L in the presence of a tertiary amine such as triethylamine. L is a leaving group which preferably is a halo group. When J or K is CO.sub.2 R.sup.7 and R7=H then Y in the resultant products is oxygen. The transformations illustrated in scheme 7 with intermediate (16) are analogous to transformations which can be employed to synthesize similarly substituted benzodiazepines. ##STR34##
Scheme 7 also provides an alternate route to generate products (I) wherein Y is NR.sup.16. In this sequence N-protected amino acids are used to acylate intermediate 1) wherein J or K is NR.sub.16, by employing either an acyl halide, or a standard carboxyl activating reagent such as dicyclohexylcarbodiimide (DCC) or (benzotriazol-1-yl)oxytris(dimethylamino) phosphonium hexafluorophosphate (BOP). The N-protecting group of the amino acid such as the carbobenzyloxy (Cbz), t-butoxycarbonyl (t-BOC) or the fluorenylethylmethoxyloxycarbonyl (FMOC) group is removed according to standard peptide synthetic conditions. The final ring forming step is made by heating this intermediate in an alcoholic solvent or by saponifying the imidazole CO.sub.2 R.sup.7 group to yield a carboxylic acid which is reacted with NR.sup.16 using carboxyl activating reagents such as DCC or polyphosphoric acid.
Following the methodology of the above described transformation of Scheme 7, if J and K are SH and CO.sub.2 R.sup.7, as illustrated by intermediate (23), and the ring forming reagent is HNR.sup.16 C(R.sup.14)(R.sup.15)CH.sub.2 C1, it is possible to form products of formula (I) wherein A is --CON(R.sup.16)--C(R.sup.14)(R.sup.15)--CH.sub.2 --W or --W--CH.sub. --C(R.sup.14) (R.sup.15)--N(R.sup.16)CO--and W is S.
The preparation of products (I) wherein A is --CON(R.sup.16)--C(R.sup.14)(R.sup.15)--C(R.sup.9).dbd.N--is carried out in Scheme 8. The final ring closure which involves a dehydration to yield an amine can be assisted by heating in the presence of molecular sieves and acetic acid in an inert solvent such as dioxane or employing polyphosphoric acid as the dehydrating agent. ##STR35##
Compounds of formula (Ia) where Q is NH.sub.2 and T is CO.sub.2 R.sup.23 are prepared as shown in Scheme 9. Imidate (12) (prepared as described in Scheme 4) is converted to amidine 28 which is sequentially alkylated and cyclized by treatment with sodium hydride and agent (2) to give intermediate (29). Scheme 9 also illustrates the deprotection of intermediate (29) where R.sup.1 is either tetrazole or CO.sub.2 tBu. ##STR36##
Acylation of intermediate (29) can be accomplished by treatment with an acid chloride as shown in Scheme 10. Amide (30) is then obtained after appropriate deprotection of R.sup.1 as described in Scheme 9. ##STR37##
Alkylation of intermediate (29) is accomplished by treatment with a strong base such as sodium hydride and an alkylating agent as indicated by Scheme 11. A second alkyl group can be introduced by the same method with intermediate (31) as substrate. Deprotection of R.sup.1 affords the mono-and di-alkylated compounds (33) and (34), respectively. ##STR38##
Alkylation of (29) with a bidentate alkylating agent, as shown in Scheme 12, leads to cyclization. Compound (35) is obtained after deprotection of R.sup.1. ##STR39##
As indicated in Scheme 13 below, mono-alkylated intermediate (31) can be subsequently acylated with an acid chloride to give, after deprotection of R.sup.1, compound (36). Acylation of (31) with chloroacetyl chloride, followed by amination with ammonia gas and treatment with di-t-butyl-dicarbonate affords intermediate (37) which, after deprotection, gives compound (38). ##STR40##
Compounds of formula I and formula Ia where R.sup.1 is --CONHSO.sub.2 R.sup.25 (where R.sup.25 =alkyl, aryl or heteroaryl may be prepared from the corresponding carboxylic acid derivatives (39) as outlined in Scheme 14. The carboxylic acid (39), obtained as described earlier can be converted into the corresponding acid chloride by treatment with refluxing thionyl chloride or preferably with oxalylchloride and a catalytic amount of dimethylformamide at low temperature [A. W. Burgstahler, L. O. Weigel, and C. G. Shaefer-Synthesis, 767, (1976)]. The acid chloride then can be treated with the alkali metal salt of R.sup.25 SO.sub.2 NH.sub.2 to form the desired acylsulfonamide 40. Alternatively, these acylsulfonamides may be also prepared from the carboxylic acids using N,N-diphenylcarbamoyl anhydride intermediates [F. J. Brown et al - European Patent Application. EP 199543: K. L. Shepard and W. Halczenko- J. Het. Chem., 16, 321 (1979)]. Preferably the carboxylic acids (39) can be converted into acyl-imidazole intermediates, which can be then treated with an appropriate aryl or alkylsulfonamide and 1,8-diazabicyclo[5.4.o]undec-7 ene (DBU) to give the desired acylsulfonamide 40 [J. T. Drummond and G. Johnson--Tetra. Lett.--29, 1653 (1988)]. ##STR41##
Compounds of formula I and formula Ia where R.sup.1 is --SO.sub.2 NHCOR.sup.25 may be prepared as outlined in Scheme 15. The nitro compound 5c (prepared as described in Scheme 2) can be reduced to the corresponding amino compound and converted into aromatic diazonium chloride salt, which then can be reacted with sulfur-dioxide in the presence of a copper (II) salt to form the corresponding arylsulfonylchloride 41 [H. Meerwein, G. Dittmar, R. Gollner, K. Hafner, F. Mesnsch and O. Steifor--Chem. Ber., 90, 841 (1957); A. J. Prinsen and H. Cerfontain, Recueil, 84, 24 (1965); E. E. Gilbert, Synthesis, 3 (1969) and references cited therein]. The sulfonyl chloride thus obtained, can be reacted with ammonia in aqueous solution or in an inert organic solvent F. H. Bergheim and W. Baker, J. Amer. Chem. Soc., 66, (1944), 1459], or with dry powdered ammonium carbonate, E. H. Huntress and J. S. Autenrieth, J. Amer. Chem. Soc., 63, (1941), 3446; E. H. Huntress and F. H. Carten, J. Amer. Chem. Soc., 62, (1940), 511]to form the sulfonamide 42. The benzyl bromide 44 may be prepared from the sulfonamide 43b as outlined in Scheme 8, and then can be reacted with an alkali metal salt of an appropriate heterocyclic compound (HET) to form the key sulfonamide 45. The sulfonamide 45 may be also prepared from the aromatic sulfonyl chloride 50, which may be prepared (where applicable) from the aryl amine 49 as outlined in Scheme 16. The acylation of 45 with appropriate acyl chlorides (or acyl-imidazoles of other acylating agents) may produce the desired acylsulfonamides 46. ##STR42##
The compounds bearing R.sup.1 as -SO.sub.2 NHR.sup.25 (where R.sup.25 is heteroaryl) may be prepared by reacting the aromatic sulfonyl chloride 50 with appropriate heteroaryl amines as outlined in Scheme 16. The sulfonyl chloride 50 may be the prefered intermediate for the synthesis of this glass of compounds. The aromatic sulfonyl chlorides may also be prepared by reacting the sodium salt of aromatic sulfonic acids with PCl.sub.5 or POCl.sub.3 [C. M. Suter, The Organic Chemistry of Sulfur. John Wiley & Sons, 459, (1944)]. The aromatic sulfonic precursors may be prepared by chlorosulfonation of the aromatic ring with chlorosulfonic acid [E. H. Huntress and F. H. Carten, J. Amer. Chem. Soc., 511 (1940)].
The biaryl sulfonamide 43a and can be prepared alternatively using palladium(0) catalyzed cross-coupling reactions of appropriate aryl-organotin precursors [J. K. Stille, Pure Appl. Chem., 1771 (1985); T. R. Baiely, Tetra Lett., 27, 4407 (1986); D. A. Widdowson and Y. Z. Zhang, Tetrahedron, 42, 2111 (1986)], as outlined in Scheme 17. The organotin compound 53 [S. M. Moerlein, J. Organometallic Chem., , 29 (1987) , obtained from the aromatic precursce , may be coupled with aryl sulfonamide 55 or 56 using Pd(PPh.sub.3).sub.4 or (PPh.sub.3).sub.2 PdCl.sub.2 as catalysts to give biaryl sulfonamides 43a and 43b, respectively. Similarly, the benzyl bromide 44a and 44b may be alternatively prepared from the appropriate organotin precursor 59 using the Pd(0) catalyzed cross-coupling reaction as outlined in Scheme 18. ##STR43##
The compounds of formula I and Ia bearing R.sup.1 =--CH.sub.2 SO.sub.2 NHCOR.sup.25 and --CH.sub.2 SO.sub.2 NHR.sup.25 may be prepared as outlined in Scheme 19. The key precursor aryl-methanesulfonyl chloride 66 may be prepared either from the reaction of aryl-methylmagnesium chloride 65 (which may be obtained from the corresponding benzyl chloride 62) with sulfuryl chloride [S. N. Bhattacharya, C. Eaborn and D. P. M. Walton, J. Chem. Soc. C, 1265 (1968)], or by oxidation of the aryl-methylthioacetate 64 (may be prepared from the benzyl bromide 63 as outlined) with chlorine in presence of trace amount of water [Bagnay and Dransch, Chem. Ber., 93, 784 (1960)]. Alternatively, the aryl-methylthioacetate 64 can be oxidized with sulfuryl chloride in presense of acetic anhydride to form aryl-methylsulfinyl chloride [S. Thea and G. Cevasco, Tetra. Lett., 28, 5193 (1987)], which can be further oxidized with appropriate oxidizing agents to give the sulfonyl chloride 66. The compounds 67 and 68 can be obtained by reacting the sulfonyl chloride 66 with appropriate amines.
Compounds of formula I and Ia where R.sup.1 =--NHSO.sub.2 NHR.sup.25 may be prepared by the reaction of appropriate primary amines with the sulfamide 71 [S. D. McDermott and W. J. Spillane, Synthesis, 192 (1983)], as described in Scheme 20. The compound 70 may be obtained from the corresponding N t-butylsulfamide 69 after treatment with anhydrous trifluoro-acetic acid [J. D. Catt and W. L. Matier, J. Org. Chem., 39, 566 (1974)], which may be prepared by the reaction of the aromatic amine 49 with t-butylsulfamoyl chloride [W. L. Matier, W. T. Comer and D. Deitchman, J. Med. Chem., 15, 538 (1972)]. ##STR44##
It will be appreciated by those skilled in the art that the protecting groups used in these syntheses will be chosen to be compatible with subsequent reaction conditions. Ultimately, they will be removed to generate the active compounds of formulae (I) and (Ia). For example. R.sup.1 as carboxyl is often protected as its t-butyl ester which in the last step is removed by treatment with trifluoroacetic acid. Aqueous acetic acid employed overnight is a preferred method to remove a trityl protecting group to liberate an R.sup.1 tetrazole group.
The compounds of this invention form salts with various inorganic and organic acids and bases which are also within the scope of the invention. such salts include ammonium salts, alkali metal salts like sodium and potassium salts, alkaline earth metal salts like the calcium and magnesium salts, salts with organic bases; e.g., dicyclohexylamine salts, N-methyl-D-glucamine, salts with amino acids like arginine, lysine, and the like. Also, salts with organic and inorganic acids may be prepared; e.g., HCl, HBr, H.sub.2 SO.sub.4, H.sub.3 PO.sub.4, methanesulfonic, toluenesulfonic, maleic, fumaric, camphorsulfonic. The non-toxic, physiologically, acceptable salts are preferred, although other salts are also useful; e.g., in isolating or purifying the product.
The salts can be formed by conventional means such as by reacting the free acid or free base forms of the product with one or more equivalents of the appropriate base or acid in a solvent or medium in which the salt is insoluble, or in a solvent such as water which is then removed in vacuo or by freeze-drying or by exchanging the cations of an existing salt for another cation on a suitable ion exchange resin.
Angiotensin II (AII) is a powerful arterial vasoconstrictor, and it exerts its action by interacting with specific receptors present on cell membranes. The compounds described in the present invention act as competitive antagonists of AII at the receptors In order to identify AII antagonists and determine their efficacy in vitro, the following two ligand-receptor binding assays were established.
Three frozen rabbit aortae (obtained from Pel-Freeze Biologicals) were suspended in 5mM Tris-0 25M Sucrose, pH 7.4 buffer (50 ml) homogenized, and then centrifuged. The mixture was filtered through a cheesecloth and the supernatant was centrifuged for 30 minutes at 20,000 rpm at 4.degree. C. The pellet thus obtained was resuspended in 30 ml of 50 mM Tris-5 mM MgCl.sub.2 buffer containing 0.2% Bovine Serum Albumin and 0.2 mg/ml Bacitracin and the suspension was used for 100 assay tubes. Samples tested for screening were done in duplicate. To the membrane preparation (0.25 ml) there was added .sup.125 I-Sar.sup.1 I1e.sup.8 -angiotensin II [obtained from New England Nuclear](10ml; 20,000 cpm) with or without the test sample and the mixture was incubated at 37.degree. C. for 90 minutes. The mixture was then diluted with ice-cold 50 mM Tris-0.9% NaCl, pH 7.4 (4 ml) and filtered through a glass fiber filter (GF/B Whatman 2.4" diameter). The filter was soaked in scintillation cocktail (10 ml) and counted for radioactivity using Packard 2660 Tricarb liquid scintillation counter. The inhibitory concentration (IC.sub.50) of potential AII antagonists which gives 50% displacement of the total specifically bound .sup.125 I-Sar.sup.1 I1e.sup.8 -angiotensin II was presented as a measure of the efficacy of such compounds as AII antagonists.
Bovine adrenal cortex was selected as the source of AII receptor. Weighed tissue (0.1 g is needed for 100 assay tubes) was suspended in Tris.HCl (50 mM), pH 7.7 buffer and homogenized. The homogenate was centrifuged at 20,000 rpm for 15 minutes. Supernatant was discarded and pellets resuspended in buffer [Na.sub.2 HPO.sub.4 (10mM)-NaCl (120mM)-disodium EDTA (5mM) containing phenylmethane sulfonyl fluoride (PMSF)(0.1 mM)]. (For screening of compounds, generally duplicates of tubes are used). To the membrane preparation (0.5 ml) there was added 3H-angiotensin II (50 mM) (10ml) with or without the test sample and the mixture was incubated at 37.degree. C. for 1 hour. The mixture was then diluted with Tris buffer (4 ml) and filtered through a glass fiber filter (GF/B Whatman 2.4" diameter). The filter was soaked in scintillation cocktail (10ml) and counted for radioactivity using Packard 2660 Tricarb liquid scintillation counter. The inhibitory concentration (IC.sub.50) of potential AII antagonists which gives 50% displacement of the total specifically bound .sup.3 H-angiotensin II was presented as a measure of the efficacy of such compounds as AII antagonists.
The potential antihypertensive effects of the compounds described in the present invention may be evaluated using the methodology described below:
Male Charles River Sprague-Dawley rats (300-375 gm) were anesthetized with methohexital (Brevital; 50 mg/kg i.p. and the trachea was cannulated with PE 205 tubing. A stainless steel pithing rod (1.5 mm thick, 150 mm long) was inserted into the orbit of the right eye and down the spinal column. The rats were immediately placed on a Harvard Rodent Ventilator (rate--60 strokes per minute, volumn--1.1 cc per 100 grams body weight). The right carotid artery was ligated, both left and right vagal nerves were cut, and the left carotid artery was cannulated with PE 50 tubing for drug administration, and body temperature was maintained at 37.degree. C. by a thermostatically controlled heating pad which received input from a rectal temperature probe. Atropine (1 mg/kg i.v.) was then administered, and 15 minutes later propranolol (1 mg/kg i.v.). Thirty minutes later angiotensin II or other agonists were administered intravenously at 30-minute intervals and the increase in the diastolic blood pressure was recorded before and after drug or vehicle administration.
Using the methodology described above, representive compounds of the invention were evaluated and all were found to exhibit an activity of at least IC.sub.50 <50 mM thereby demonstrating and confirming the utility of the compounds of the invention as effective AII antagonists.
Thus, the compounds of the invention are useful in treating hypertension. They are also of value in the management of acute and chronic congestive heart failure. These compounds may also be expected to be useful in the treatment of secondary hyperaldosteronism, primary and secondary pulmonary hyperaldosteronism, primary and secondary pulmonary hypertension, renal failure such as diabetic nephropathy, glomerulonephritis, scleroderma, glomerular sclerosis, proteinuria of primary renal disease, end stage renal disease, renal transplant therapy, and the like, renal vascular hypertension, left ventricular dysfunction, diabetic retinopathy and in the management of vascular disorders such as migraine, Raynaud's disease, luminal hyperclasia, and to minimize the atherosclerotic process. The application of the compounds of this invention for these and similar disorders will be apparent to those skilled in the art.
The compounds of this invention are also useful to treat elevated intraocular pressure and to enhance retinal blood flow and can be administered to patients in need of such treatment with typical pharmaceutical formulations such as tablets, capsules, injectables and the like as well as topical ocular formulations in the form of solutions, ointments, inserts, gels, and the like. Pharmaceutical formulations prepared to treat intraocular pressure would typically contain about 0.1% to 15% by weight, preferably 0.5% to 2% by weight, of a compound of this invention.
In the management of hypertension and the clinical conditions noted above, the compounds of this invention may be utilized in compositions such as tablets, capsules or elixirs for oral administration, suppositories for rectal administration, sterile solutions or suspensions for parenteral or intramuscular administration, and the like. The compounds of this invention can be administered to patients (animals and human) in need of such treatment in dosages that will provide optimal pharmaceutical efficacy. Although the dose will vary from patient to patient depending upon the nature and severity of disease, the patient's weight, special diets then being followed by a patient, concurrent medication, and other factors which those skilled in the art will recognize, the dosage range will generally be about 1 to 1000 mg. per patient per day which can be administered in single or multiple doses. Perferably, the dosage range will be about 2.5 to 250 mg. per patient per day; more preferably about 2.5 to 75 mg. per patient per day.
The compounds of this invention can also be administered in combination with other antihypertensives and/or diuretics and/or angiotensin converting enzyme inhibitors and/or calcium channel blockers. For example, the compounds of this invention can be given in combination with such compounds as amiloride, atenoolol, bendroflumethiazide, chlorothalidone, chlorothiazide, clonidine, cryptenamine acetates and cryptenamine tannates, deserpidine, diazoxide, guanethidene sulfate, hydralazine hydrochloride, hydrochlorothiazide, metolazone, metoprolol tartate, methyclothiazide, methyldopa, methyldopate hydrochloride, minoxidil, pargyline hydrochloride, polythiazide, prazosin, propranolol, rauwolfia serpentina, rescinnamine, reserpine, sodium nitroprusside, spironolactone, timolol maleate, trichlormethiazide, trimethophan camsylate, benzthiazide, quinethazone, ticrynafan, triamterene, acetazolamide, aminophylline, cyclothiazide, ethacrynic acid, furosemide, merethoxylline procaine, sodium ethacrynate, captopril, delapril hydrochloride, enalapril, enalaprilat, fosinopril sodium, lisinopril, pentopril, quinapril hydrochloride, ramapril, teprotide, zofenopril calcium, diflusinal, diltiazem, felodipine, nicardipine, nifedipine, niludipine, nimodipine, nisoldipine, nitrendipine, and the like, as well as admixtures and combinations thereof.
Typically, the individual daily dosages for these combinations can range from about one-fifth of the minimally recommended clinical dosages to the maximum recommended levels for the entities when they are given singly.
To illustrate these combinations, one of the angiotensin II antagonists of this invention effective clinically in the 2.5-250 milligrams per day range can be effectively combined at levels at the 0.5-250 milligrams per day range with the following compounds at the indicated per day dose range: hydrochlorothiazide (15-200 mg) chlorothiazide (125-2000 mg), ethacrynic acid (15-200 mg), amiloride (5-20 mg), furosemide (5-80 mg), propranolol (20-480 mg), timolol maleate (5-60 mg.), methyldopa (65-2000 mg), felodipine (5-60 mg), nifedipine (5-60 mg), and nitrendipine (5-60 mg). In addition, triple drug combinations of hydrochlorothiazide (15-200 mg) plus amiloride (5-20 mg) plus angiotensin II antagonist of this invention (3-200 mg) or hydrochlorothiazide (15-200 mg) plus timolol maleate (5-60) plus an angiotensin II antagonist of this invention (0.5-250 mg) or hydrochlorothiazide (15-200 mg) and nifedipine (5-60 mg) plus an angiotensin II antagonist of this invention (0.5-250 mg) are effective combinations to control blood pressure in hypertensive patients. Naturally, these dose ranges can be adjusted on a unit basis is necessary to permit divided daily dosage and, as noted above, the dose will vary depending on the nature and severity of the disease, weight of patient, special diets and other factors.
Typically, these combinations can be formulated into pharmaceutical compositions as discussed below.
About 1 to 100 mg. of compound or mixture of compounds of Formula I or Formula Ia or a physiologically acceptable salt thereof is compounded with a physiologically acceptable vehicle, carrier, excipient, binder, preservative, stabilizer, flavor, etc., in a unit dosage form as called for by accepted pharmaceutical practice. The amount of active substance in these compositions or preparations is such that a suitable dosage in the range indicated is obtained.
Illustrative of the adjuvants which can be incorporated in tablets, capsules and the like are the following a binder such as gum tragacanth, acacia, corn starch or gelatin; in excipient such as microcrystalline cellulose; a disintegrating agent such as corn starch, pregelatinized starch, alginic acid and the like; a lubricant such as magnesium stearate; a sweetening agent such as sucrose, lactose or saccharin; a flavoring agent such as peppermint, oil of wintergreen or cherry. When the dosage unitform is a capsule, it may contain, in addition to materials of the above type, a liquid carrier such as fatty oil. Various other materials may be present as coatings or to otherwise modify the physical form of the dosage unit. For instance, tablets may be coated with shellac, Sugar or both A syrup or elixir may contain the active compound sucrose as a sweetning agent, methyl and propyl parabens as preservatives, a dye and a flavoring such as cherry or orange flavor.
Sterile compositions for injection can be formulated according to conventional pharmaceutical practice by dissolving or suspending the active substance in a vehicle such as water for injection, a naturally occuring vegetable oil like sesame oil, coconut oil, peanut oil, cottonseed oil, etc., or a synthetic fatty vehicle like ethyl oleate or the like. Buffers, preservatives, antioxidants and the like can be incorporated as required.
The following examples illustrate the preparation of the compounds of formulas (I) and (Ia) and their incorporation into pharmaceutical compositions and as such are not to be considered as limiting the invention set forth in the claims appended hereto.
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Continuation in Parts (1)
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360673 |
Jun 1989 |
|
Patent Grant
5064825
