Claims
- 1. A topical ophthalmologically acceptable composition useful for reducing intraocular pressure which comprises an intraocular pressure reducing effective amount of a compound represented by the formula: ##STR22## and the pharmaceutically acceptable salts thereof, wherein: A is ##STR23## K is 1 or 2; n is 0 or 1;
- p and q are 0, 1 or 2, provided that in structures IIb and IIc the sum of p and q is 1 or 2, and that in formula IId, p is not 0;
- B is -[J]-[L]-[M]-;
- D is ##STR24## E is --NH--,--O--, --S--, or --CH.sub.2 --; G is --SO.sub.2 --;
- J is --(CH.sub.2).sub.s -- or --((CH.sub.2).sub.t --W)--;
- L is a chemical bond, cis- or trans-lower alkene, lower alkyne, -Z-aryl-, -aryl-Z-, -Z-cycloalkyl-, or -cycloalkyl-Z-, wherein aryl is ##STR25## and cycloalkyl is ##STR26## wherein w is 1, 2 or 3; M is --(CH.sub.2).sub.u -- or --((CH.sub.2).sub.t --X--(CH.sub.2)v)--;
- W is ##STR27##
- X and Z are independently a chemical bond, --NR.sup.9 --, --O--, --S--, ##STR28## s, u and v are independently 0-5; t is 1-5;
- R.sup.1, R.sup.2 and R.sup.9 are independently hydrogen, lower alkyl or lower acyl;
- R.sup.3 is hydrogen, lower alkyl, halo- and dihaloloweralkyl, trifluoroethylthiomethyl, phenylloweralkyl, (cycloalkyl)loweralkyl, aminomethyl, loweralkylaminomethyl, phenyl(lower)alkylaminomethyl, (cycloalkyl)loweralkylaminomethyl, loweralkylthiomethyl or haloloweralkylthiomethyl;
- R.sup.4 is chlorine or CF.sub.3 ;
- R.sup.5 is hydrogen, halogen, lower alkyl, lower acyl, lower alkoxy, haloloweralkyl or phenylloweralkyl;
- R.sup.7 is hydrogen, lower alkyl or aminoloweralkyl;
- R.sup.6 and R.sup.8 are independently hydroxy, alkoxy having from 1 to 8 carbon atoms, benzyl, allyl, R.sup.10 --Q.sub.r --(CH.sub.2).sub.m --O--, wherein Q is oxygen or sulfur, r is 0 or 1 and m is 2 to 4, ##STR29## wherein the alkyl has from 3 to 8 carbon atoms, ##STR30## wherein the phenyl may be substituted with group T defined below, 1-glyceryl, ##STR31## R.sup.10 is phenyl, substituted phenyl wherein the substituents are chosen from group T, 1-naphthyl or 2-naphthyl;
- T is halogen, hydroxy, trifluoromethyl, lower alkoxy, lower alkyl, 2-furanyl, 3-furanyl, 2-thienyl, 3-thienyl, phenyl and substituted phenyl wherein the substituents are chosen from halogen, hydroxy, trifluoromethyl, lower alkoxy or lower alkyl;
- R.sup.11 is hydrogen or alkyl having from 1 to 8 carbon atoms;
- R.sup.12 is hydrogen, lower alkyl, unsubstituted or substituted phenyl and substituted or unsubstituted phenyl lower alkyl, wherein phenyl may be substituted by group T;
- R.sup.13 is hydrogen or lower alkyl;
- provided that if L is alkene or alkyne, J is --(CH.sub.2).sub.s -- wherein s is 1-5; provided that if L is -Z-aryl- or -Z-cycloalkyl-, J is --(CH.sub.2).sub.s -- wherein s is 2-5; provided that if L is alkene, alkyne, -aryl-Z- or -cycloalkyl-Z-, M is --(CH.sub.2).sub.u -- wherein u is 1-5; provided that if s and u are each zero, L is aryl or cycloalkyl (i.e. Z is a bond); and provided that if s and v are each zero, L is aryl or cycloalkyl (ie. Z is a bond);
- in combination with an ophthamologically acceptable carrier for topical use.
- 2. A composition according to claim 1 wherein A is of the formula IIa, IIb wherein p is zero and q is 1, or IId wherein p and q are each 1 and n is zero.
- 3. A composition according to claim 1 wherein D is of the formula IIIa wherein G is --SO.sub.2 -- and R.sup.4 is chlorine.
- 4. A composition according to claim 3 wherein R.sup.2 is hydrogen and R.sup.3 is phenylethyl, (cyclopentyl)methyl, butyl, pentyl, chloromethyl, dichloromethyl or trifluoroethylthiomethyl.
- 5. A composition according to claim 1 wherein E is --NH--.
- 6. A composition according to claim 1 wherein R.sup.7 is hydrogen, methyl or aminobutyl.
- 7. A composition according to claim 1 wherein R.sup.6 and R.sup.8 are hydroxy.
- 8. A composition according to claim 1 wherein B is ##STR32## i.e., compounds wherein J is --(CH.sub.2).sub.s -- and s is 0-1, L is a bond or -Z-aryl- wherein Z is a bond, and M is --((CH.sub.2).sub.t --X--(CH.sub.2).sub.v) wherein t is 1, v is 1-2 and X is a bond or --O--.
- 9. A composition according to claim 1 comprising a compound represented by the formula ##STR33## wherein A is formula IIa, IIb wherein p is 0 and q is 1, or IId wherein p and q are each 1 and n is 0, and R.sup.3 is phenylethyl, chloromethyl, dichloromethyl, butyl, pentyl, (cyclopentyl)methyl, or trifluoroethylthiomethyl.
- 10. The composition of claim 1 wherein the compound is 1-[2-(S)-[[1(S)-carboxy-5-[[6-chloro-3-chloromethyl-3,4-dihydro-2H-1,2,4-benzothiadiazin-7-yl]sulfonylamino]pentyl]amino]-1-oxopropyl]-[2S(2.alpha., 3a.alpha.,7a.alpha.)]-octahydro-1H-indole-2-carboxylic acid, S,S-dioxide.
BACKGROUND OF THE INVENTION
This application is a continuation-in-part of Ser. No. 653,186, filed Sept. 24, 1984, now U.S. Pat. No. 4,556,655.
The present invention relates to ophthalmological pharmaceutical compositions comprising carboxyalkyl dipeptides joined through a sulfonamido group to a benzothiadiazinyl sulfonylphenyl moiety and to a method for using said composition in the treatment of glaucoma.
Glaucoma is an ocular disease complex associated with an elevated pressure within the eye (i.e., intraocular pressure, IOP). As a result of the elevated IOP, damage to the optic nerve head resulting in irreversible loss of visual function may ensue. Untreated, this condition may eventually lead to blindness.
Ocular hypertension, i.e., the condition of elevated intraocular pressure without optic nerve head damage or characteristic glaucomatous visual field loss, is now believed by the majority of ophthalmologists to represent the earliest phase in the onset of glaucoma.
A number of the drugs presently employed to treat glaucoma are not entirely satisfactory. particularly in the earliest course of the disease when the side effects they produce are often worse than the symptoms of the disease.
Epinephrine, used as a topical solution, must be utilized cautiously in patients with high blood pressure, diabetes, hyperthyroidism and cerebral artereosclerosis due to the possibility of systemic action.
Timolol, a clinically utilized, topically applied agent for lowering intraocular pressure, must be used with caution in patients in whom beta-adrenergic blockade may be undesirable. Systemic absorption of topically administered timolol and systemic beta-blockade are responsible for the contraindication of timolol therapy for glaucoma in patients with compromised pulmonary function and in patients who cannot tolerate its systemic cardiovascular action.
Pilocarpine, a topical drug, although considered systemically harmless and quite effective, may cause considerable local difficulties. Pupil constriction causes the eye to lose its ability to adapt from light to dark. Accomodation may become stimulated so that the patient's refraction is sometimes incorrect and vision becomes blurred. The drug itself may cause a local vasodilation and red eyes. Irritation is common.
Carbonic anhydrase inhibitors have been used systemically but they have a number of disadvantages. While effective in lowering intraocular pressure, they often cause a numbness and tingling, gastrointestinal upsets and, frequently, depression, lethargy, a loss of appetite, and general malaise. European Patent Application No. 81400326.5, Publication number 36,351 attempts to overcome these difficulties by the topical administration of an alkali metal salt of a carbonic anhydrase inhibitor.
The present invention provides a new method for reducing and controlling the elevated intraocular pressure associated with glaucoma.
The invention sought to be patented in its pharmaceutical composition aspect is a topical ophthalmologically acceptable composition useful for reducing and controlling the elevated intraocular pressure associated with glaucoma which comprises an intraocular pressure reducing effective amount of a compound comprising a carboxyalkyl dipeptide joined through a sulfonamido group to a benzothiadiazinyl or sulfonylphenyl moiety as described below in combination with an ophthalmologically acceptable carrier for topical use.
The invention sought to be patented in its pharmaceutical method aspect is a method for reducing and controlling the elevated intraocular pressure associated with glaucoma in a human which method comprises administering to said human an effective amount of the above-defined pharmaceutical composition.
The compounds contemplated for use in the compositions of this invention have the following structural formula: ##STR1## and the pharmaceutically acceptable salts thereof, wherein:
A is ##STR2##
l is 1 or 2;
n is 0 or 1;
p and q are 0, 1 or 2, provided that in structures IIb and IIc the sum of p and q is 1 or 2, and that in formula IId, p is not 0;
B is -[J]-[L]-[M]-;
D is ##STR3##
E is --NH--,--O--, --S--, or --CH.sub.2 --;
G is ##STR4## or --SO.sub.2 --;
J is --(CH.sub.2).sub.s -- or --((CH.sub.2).sub.t --W)--;
L is a chemical bond, cis- or trans-lower alkene, lower alkyne, -Z-aryl-, -aryl-Z-, -Z-cycloalkyl-, or -cycloalkyl-Z-, wherein aryl is ##STR5## and cycloalkyl is ##STR6## wherein w is 1, 2 or 3;
M is --(CH.sub.2).sub.u --or --((CH.sub.2).sub.t --X--(CH.sub.2).sub.v)--;
W is ##STR7##
X and Z are independently a chemical bond, --NR.sup.9 --, --O--, --S--, ##STR8##
s, u and v are independently 0-5;
t is 1-5;
R.sup.1, R.sup.2 and R.sup.9 are independently hydrogen, lower alkyl or lower acyl;
R.sup.3 is hydrogen, lower alkyl, halo- and dihaloloweralkyl, trifluoroethylthiomethyl, phenylloweralkyl, (cycloalkyl)lower alkyl, aminomethyl, lower alkylaminomethyl, phenylloweralkylaminomethyl,(cycloalkyl)loweralkylaminomethyl, loweralkylthiomethyl or haloloweralkylthiomethyl;
R.sup.4 is chlorine or CF.sub.3 ;
R.sup.5 is hydrogen, halogen, lower alkyl, lower acyl, lower alkoxy, haloloweralkyl or phenylloweralkyl;
R.sup.7 is hydrogen, lower alkyl or aminoloweralkyl;
R.sup.6 and R.sup.8 are independently hydroxy, alkoxy having from 1 to 8 carbon atoms, benzyl, allyl, R.sup.10 --Q.sub.r --(CH.sub.2).sub.m --O--, wherein Q is oxygen or sulfur, r is 0 or 1 and m is 2 to 4, ##STR9## wherein the alkyl has from 3 to 8 carbon atoms, ##STR10## wherein the phenyl may be substituted with group T defined below, 1-glyceryl, ##STR11##
R.sup.10 is phenyl, substituted phenyl wherein the substituents are chosen from group T, 1-naphthyl or 2-naphthyl;
T is halogen, hydroxy, trifluoromethyl, lower alkoxy, lower alkyl, 2-furanyl, 3-furanyl, 2-thienyl, 3-thienyl, phenyl and substituted phenyl wherein the substituents are chosen from halogen, hydroxy, trifluoromethyl, lower alkoxy or lower alkyl;
R.sup.11 is hydrogen or alkyl having from 1 to 8 carbon atoms;
R.sup.12 is hydrogen, lower alkyl, unsubstituted or substituted phenyl and substituted or unsubstituted phenyl lower alkyl wherein phenyl may be substituted by group T;
R.sup.13 is hydrogen or lower alkyl;
provided that if L is alkene or alkyne, J is --(CH.sub.2).sub.s -- wherein s is 1-5; provided that if L is -Z-aryl- or -Z-cycloalkyl-, J is --(CH.sub.2).sub.s -- wherein s is 2-5; provided that if L is alkene, alkyne, -aryl-Z- or -cycloalkyl-Z-, M is --(CH.sub.2).sub.u -- wherein u is 1-5; provided that if s and u are each zero, L is aryl or cycloalkyl (i.e. Z is a bond); and provided that if s and v are each zero, L is aryl or cycloalkyl (i.e. Z is a bond);
with the further provision that when D is of formula IIIb and R.sup.1 is hydrogen, B is not --(CH.sub.2).sub.4 --; and that when D is of formula IIIb and R.sup.1 is hydrogen or lower alkyl, B is not --(CH.sub.2).sub.s --aryl--(CH.sub.2).sub.t --X--(CH.sub.2).sub.v -- wherein s is 0 or 1, t is 1, v is 0 to 2 and X is a bond, --O--, or --S--.
When A is formula IIb or IIc, the preferred sum of p and q is 1; when A is of formula IId, preferred of p and q is 1; when A is of formula IId, preferred values for each of p and q are 1. Compounds wherein A is IIa or IIb wherein p is 0 and q is 1, and IId wherein p and q are each 1 and n is zero are preferred.
Also preferred are compounds wherein D is of formula IIIa, with compounds wherein R.sup.4 is chlorine and G is --SO.sub.2 -- being more preferred. Another group of preferred compounds are those wherein D is of formula IIIa, R.sup.4 is chlorine, G is --SO.sub.2 --, R.sup.2 is hydrogen and R.sup.3 in phenylethyl, (cyclopentyl)methyl, chloromethyl, dichloromethyl, butyl, pentyl, or trifluoroethylthiomethyl.
Also preferred are compounds wherein B is ##STR12## i.e., compounds wherein J is --(CH.sub.2).sub.s -- and s is 0-1, L is a bond or -Z-aryl- wherein Z is a bond, and M is --((CH.sub.2).sub.t --X--(CH.sub.2).sub.v), wherein t is 1, v is 1-2, and X is a bond or --O--.
A preferred group for E is --NH--.
Another group of preferred compounds are those wherein R.sup.7 is hydrogen, methyl or aminobutyl. Still another group of preferred compounds are those wherein R.sup.6 and R.sup.8 are hydroxy.
As used herein, "lower alkyl" means straight or branched chain hydrocarbon radicals of from 1 to 6 carbons, e.g. methyl, ethyl, propyl, isopropyl, butyl, t-butyl, pentyl and hexyl. Similarly, "lower alkoxy" means straight or branched alkoxy radicals having from 1 to 6 carbon atoms, e.g. methoxy, ethoxy, propoxy, butoxy, iso-butoxy, pentoxy and hexyloxy. "Halogen" means fluorine, chlorine and bromine. "Lower acyl" means organic radicals obtained by removing the hydroxyl group from the corresponding carboxylic acid of from 1 to 6 carbons, e.g. formyl, acetyl, propionyl and butyryl. "Lower alkene" means unsaturated hydrocarbon radicals of from 2 to 6 carbon atoms having one double bond, e.g. vinylene propenyl, butenyl, pentenyl and hexenyl, wherein the double bond may be present anywhere in the chain, e.g. 1-or 2-propenyl, 1-, 2- or 3-butenyl. Similarly, "lower alkyne" means a hydrocarbon radical of from 2 to 6 carbon atoms having one triple bond, e.g. ethynylene, propynyl, butynyl, pentynyl and hexynyl, wherein the triple bond may be present anywhere in the chain, e.g. 1- or 2-propynyl, 1-, 2- or 3-butynyl.
Compounds of the instant invention include various stereoisomers. Preferred stereoisomers are those in which the absolute configuration at carbon atoms adjacent to both a nitrogen and a carbonyl group corresponds most closely to the absolute configuration of L-amino acids.
Preferred examples of compounds of formula I are as follows:
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, e.g. calcium and magnesium salts. Salts with organic bases may be prepared, e.g., N-methylglucamine, lysine and arginine, as well as salts with organic and inorganic acids, e.g., HCl, HBr, H.sub.2 SO.sub.4, H.sub.3 PO.sub.4, methanesulfonic acid, toluenesulfonic acid, maleic acid, fumaric acid and camphorsulfonic acid. The non-toxic pharmaceutically acceptable salts are preferred, although other salts are also useful, e.g., in isolating or purifying the product. The acid salts (e.g. HCl and maleate) are preferred, especially the hydrochloride.
The salts may be formed by conventional means, as by reacting the free acid or 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 exchanging the cations of an existing salt for another cation on a suitable ion exchange resin.
Compounds of formula I may be prepared by several routes using methods known in the art.
For example, compounds of formula I can be prepared by condensing an acid of formula IV (or its hydrochloride salt) with an amino acid derivative of formula V: ##STR13## wherein R.sup.1,R.sup.6, R.sup.7, R.sup.8, D, B, E and A are as defined above. The reaction is carried out in an inert solvent such as dimethylformamide (DMF) in the presence a condensing agent such as 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide hydrochloride (DEC) and 1-hydroxybenzotriazole, and where the compound of formula IV is a salt in the presence of a base such as triethylamine. The reaction is preferably carried out in an inert atomsphere at a temperature of 0.degree.-25.degree. C.
Compounds of formula V are known in the art, or may be prepared by methods well known to those skilled in the art.
Compounds of formula IV may be prepared for example from the reaction of a sulfonyl chloride of formula VI and an amine of formula VII: ##STR14## wherein D, B, E, R.sup.1, R.sup.6 and R.sup.7 are as defined above and R.sup.14 is a readily removable ester protecting group such as t-butyl, benzyl or trimethylsilylethyl. The reaction is carried out at 0.degree.-5.degree. C. in a solvent such as tetrahydrofuran (THF).
Compounds of formula VI may be prepared from known starting materials using procedures well known in the art. For example, when D is of the formula IIIa wherein G is SO.sub.2 and R.sup.3 is phenylethyl, the sulfonyl chlorides of formula VI may be obtained by reacting a disulfonyl chloride of formula VIII with aqueous ammonia at low temperature (dry-ice-acetone bath) in a solvent such as 1,2-dimethoxyethane (DME) in the presence of a base such as triethylamine to obtain a sulfonamide of formula IX, followed by reaction of the sulfonamide with phenyl propanal in a solvent such as DME and in the presence of an acid such as p-toluenesulfonic acid: ##STR15##
Similarly, when D is of formula IIIb, the sulfonyl chlorides of formula VI may be obtained by well known procedures. A typical reaction scheme follows: ##STR16##
Compounds of formula VII are prepared from known starting materials using methods known in the art. A typical reaction scheme is shown below for compounds of formula VIIb, wherein R.sup.1 is hydrogen, R.sup.6 is lower alkyl, R.sup.7 is methyl, J is --(CH.sub.2)--, L is phenyl, M is --CH.sub.2 --O--CH.sub.2 --, E is --NH--, and R.sup.14 is as defined above: ##STR17##
Details of the above typical reaction scheme are disclosed in Example 1, Parts A-E.
In the above reaction scheme, the triflate reagent, i.e. t-butyl 2(S)-(trifluoromethanesulfonyloxy)propionate, reacts by nucleophillic displacment with the .alpha.-aminoacid ester to give a high yield of the corresponding specific diastereomer of the resulting monoamino dicarboxylic acid ester. Compounds of formula VIId, wherein M is (CH.sub.2).sub.2 and R.sup.1, R.sup.6, R.sup.7, R.sup.14, J, L and E are as described above for formula VIIb, may be prepared as follows: ##STR18##
The above reaction scheme is exemplified ln Parts A-C of Example 3.
A typical reaction scheme for the preparation of compounds of formula VIIf wherein L is a bond, J is --(CH.sub.2).sub.s --and M is --(CH.sub.2).sub.u)-- wherein the sum of s and u is 4, and R.sup.1, R.sup.6, R.sup.7, R.sup.14 and E are as described above for formula VIIb is as follows: ##STR19## Example 5 provides details of this procedure.
Alternatively, intermediates of formulae VIIa or VIIc may be used to prepare compounds of formula I as follows: The R.sup.14 protecting groups (e.g. t-butoxycarbonyl) of compounds of formulae VIIa or VIIc may be removed, e.g. by trifluoroacetic acid, and the nitrile reacted with an amino acid derivative of formula V under the conditions described on page 7. The resulting nitrile can then be reduced to the corresponding amine, e.g., by hydrogenation, which amine can then in turn be coupled to a sulfonyl chloride of formula VI by conventional methods. Similarly, intermediates of formula VIIe (i.e., compounds of formula VII wherein B is alkyl) may be deprotected at the carboxylic acid group and condensed with the amino acid derivative of formula V as described above, then deprotected at the amino group, e.g. by hydrogenation, and the resultant amine reacted with a sulfonyl chloride of formula VI by conventional methods.
Another method for preparing compounds of formula IV is that exemplified below for preparing compounds wherein D is of formula IIIa wherein G is --SO.sub.2 --, J is --CH.sub.2 --, L is --aryl-Z-- wherein aryl is phenyl and Z is ##STR20## M is --CH.sub.2 --, E is --NH--, R.sup.1 is hydrogen, R.sup.6 is ethyl, R.sup.7 is methyl, and R.sup.2, R.sup.3 and R.sup.4 are as defined above: ##STR21## Example 7 incorporates the above procedure.
The known coupling methods above include amino group protection during the coupling reaction, for example with protecting groups such as N-formyl, N-t-butoxycarbonyl (t-Boc) and N-carbobenzyloxy (Cbz) groups, followed by their removal to yield compounds of formula I. Furthermore, the COR.sup.8 function wherein R.sup.8 is OH may be protected by removable ester groups such as benzyl, ethyl, t-butyl, trimethylsilylethyl and the like.
The more complex esters at R.sup.6 (i.e., R.sup.6 is other than hydroxy or alkoxy) are most conveniently prepared by esterifying compounds compounds of formula I wherein R.sup.6 is hydroxy and R.sup.8 is a protected hydroxy, e.g. benzyloxy, with the appropriate reagents, e.g. chloromethyl pivalate in the presence of base, to obtain the corresponding pivaloyloxymethyl ester; the benzyl group is then removed by conventional means, e.g. catalytic hydrogenation.
US Referenced Citations (4)
Continuation in Parts (1)
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Number |
Date |
Country |
| Parent |
653186 |
Sep 1984 |
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Patent Grant
4634698
