Claims
- 1. A process for the treatment of a cognitive dysfunction in a mammal, comprising the step of administering to a mammal for the purpose of said treatment, an effective amount of an angiotension-converting enzyme inhibitor of the formula (II) or a physiologically tolerated salt thereof, ##STR78## in which n is 1 or 2;
- R denotes hydrogen, an aliphatic radical having 1-21 carbon atoms, an aromatic radical having 6-12 carbon atoms,
- R.sup.1 denotes hydrogen, an aliphatic radical having 1-21 carbon atoms, or, if not already covered by the above definitions, the side-chain, protected where necessary, of a naturally occurring .alpha.-amino acid,
- R.sup.2 and R.sup.3 are identical or different and denote hydrogen, an aliphatic radical having 1-21 carbon atoms, an alicyclic radical having 3--20 carbon atoms, an aromatic radical having 6.14 12 carbon atoms, an araliphatic radical having 7-32 carbon atoms, and
- R.sup.4 and R.sup.5 form, together with the atoms carrying them, a heterocyclic ring system selected from pyrrolidine, octahydroindole, and octahydrocyclopenta[b]pyrrole.
- 2. The process as claimed in claim 1, wherein said compound of formula (II) is (S,S,S,S,S)-1-[N-(1-carbethoxy-3-phenylpropyl)-alanyl]-octahydroindole-2-carboxylic acid, 1-[N-(1-S-carbethoxy-3-phenylpropyl)-S-alanyl]-(2S,3aR,7aS)-octahydroindole-2-carboxylic acid, or (S,S,S,S,S)-2-[N-(1-carbethoxy-3-phenylpropyl)-alanyl]-2-azabicyclo[3.3.0]-octane-3-carboxylic acid.
Priority Claims (1)
| Number |
Date |
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Kind |
| 3610391 |
Mar 1986 |
DEX |
|
Parent Case Info
This application is a division of application Ser. No. 07/362,288 filed Jun. 6, 1989, which is a continuation of application Ser. No. 07/226,521 filed Aug. 1, 1989, which is a continuation of application Ser. No. 07/029,905 filed Mar. 25, 1987, all now abandoned.
The invention relates to the use of angiotensin converting enzyme inhibitors (ACE inhibitors) or their physiologically tolerated salts as medicaments having a cognition adjuvant action (improving cognitive function) and to the use thereof in the preparation of corresponding pharmaceutical formulations.
Examples of suitable compounds for this novel use are those of the formula I
An optionally substituted aliphatic radical is understood to be an aliphatic acyclic radical, i.e. a radical with an open, straight or branched carbon chain such as, for example, alkyl, alkenyl, alkynyl and corresponding multiply unsaturated radicals. It is preferably unsubstituted or, as described below, for example, for carboxyl, carbamoyl, aminoalkyl, alkanoylaminoalkyl, alkoxycarbonylaminoalkyl, arylalkoxycarbonylaminoalkyl, arylalkylaminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, alkylthioalkyl, arylthioalkyl, carboxyalkyl, carbamoylalkyl, alkoxycarbonylalkyl, alkanoyloxyalkyl, alkoxycarbonyloxyalkyl, aroyloxyalkyl or aryloxycarbonyloxyalkyl, monosubstituted.
An optionally substituted alicyclic radical, and the corresponding optionally substituted alicyclic-aliphatic radical which is linked via an open carbon chain, is a preferably mono- to pentacyclic, isocyclic, nonaromatic radical which has single bonds or asymmetrically distributed double bonds and can also be branched (i.e. carry open-chain aliphatic side-chains) and is linked via a ring carbon atom or a side-chain carbon atom. It is preferably unsubstituted. When several rings are components of a radical of this type, they are fused, spiro-linked or isolated. Examples of radicals of this type are cycloalkyl, cycloalkenyl, cycloalkylalkyl, bicycloalkyl, tricycloalkyl and radicals derived from mono-, bi- or oligocyclic terpenes such as menthyl, isomenthyl, bornanyl, bornyl, caranyl, epibornyl, epiisobornyl, isobornyl, menthanyl, neomenthyl, neoisomenthyl, pinanyl and thujanyl; they are preferably unsubstituted (according to the present definition, aliphatic side-chains are not substituents).
An optionally substituted aromatic radical is preferably aryl such as phenyl, biphenylyl or naphthyl, which is optionally mono-, di- or trisubstituted as indicated below for aryl. Radicals derived from aryl, such as aralkyl, aryloxy, arylthio or aroyl, preferably benzoyl, can be substituted as for aryl.
An optionally substituted heteroaromatic radical is preferably an aromatic mono- or bicyclic heterocyclic radical having 5 to 7 or 8 to 12, preferably up to 10, ring atoms respectively, 1 or 2 of these ring atoms representing sulfur or oxygen atoms and/or 1 to 4 of these ring atoms representing nitrogen atoms, and is understood to be, for example, thienyl, benzo[b]thienyl, furyl, pyranyl, benzofuryl, pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyridazinyl, indazolyl, isoindolyl, indolyl, purinyl, quinolizinyl, isoquinolinyl, phthalazinyl, naphthyridinyl, quinoxalinyl, quinazolyl, cinnolinyl, pteridinyl, oxazolyl, isoxazolyl, thiazolyl or isothiazolyl. These radicals can also be partially or completely hydrogenated. A heteroaromatic radical and the corresponding heteroaromaticaliphatic radical can be substituted as defined below.
An optionally substituted araliphatic radical is understood to be, in particular, aralkyl radicals such as arylalkyl, diarylalkyl, indanyl or fluorenyl, in which aryl is as defined above and which can be substituted in the manner indicated there.
R.sup.4 and R.sup.5 can form, with the atoms carrying them, a mono-, bi- or tricyclic heterocyclic ring system which has 3 to 15 ring carbon atoms and preferably has up to 2 sulfur atoms and up to 2 nitrogen atoms in the ring, in particular up to 1 sulfur atom.
Particularly suitable ring systems of these types are those of the following group:
Pyrrolidine (O); thiazolidine (R); tetrahydroisoquinoline (A); decahydroisoquinoline (B); octahydroindole (C); indoline (Q); octahydrocyclopenta[b]pyrrole (D); 2-azaspiro[4.5]decane (E); 2-azaspiro[4.4]nonane (F); spiro[(bicyclo[2.2.1]heptane)-2,3'-pyrrolidine] (G); spiro[(bicyclo[2.2.2]octane)-2,3'-pyrrolidine] (H); 2-azatricyclo[4.3.0.1.sup.6,9 ]decane (I); decahydrocyclohepta[b]pyrrole (J); octahydroisoindole (K); octahydrocyclopenta[c]pyrrole (L); 2,3,3a,4,5,7a-hexahydroindole (M); 2-azabicyclo[3.1.0]hexane (N); 1,2,3,3a,4,6a-hexahydrocyclopenta[b]pyrrole (P), all of which can optionally be substituted. Pyrrolidine (O) and thiazolidine (R); can be monosubstituted by, for example, (C.sub.6 -C.sub.12)-aryl, (phenyl, 2-hydroxyphenyl etc.), (C.sub.6 -C.sub.12)-arylmercapto (such as phenylmercapto) or (C.sub.3 -C.sub.7)-cycloalkyl (such as cyclohexyl). Tetrahydroisoquinoline (A) can carry, for example, in the aryl moiety, up to 2 (C.sub.1 -C.sub.6)-alkoxy radicals, preferably methoxy radicals. A corresponding statement applies to the other ring systems. However, the unsubstituted systems are preferred.
With compounds of the formula I or II which have several chiral atoms all possible diastereomers, as racemates or enantiomers, or mixtures of various diastereomers are suitable.
The suitable heterocyclic ring systems have the following structural formulae. ##STR6##
A preferred embodiment comprises use of compounds of the formula I, preferably those of the formula II, in which
A particularly preferred embodiment comprises use of compounds of the formula I, preferably those of the formula II,
If R.sup.1 represents a side-chain of a protected naturally occurring .alpha.-amino acid, such as, for example, protected Ser, Thr, Asp, Asn, Glu, Gln, Arg, Lys, Hyl, Cys, Orn, Cit, Tyr, Trp or His, preferred protective groups are the groups customary in peptide chemistry (cf. Houben-Weyl, vol. XV/1 and XV/2). In the case where R.sup.1 denotes the protected side-chain of lysine, the known amino protective groups are preferred, but in particular Z, Boc or (C.sub.1 -C.sub.6 )-alkanoyl. Suitable and preferred O-protective groups for tyrosine are (C.sub.1 -C.sub.6)-alkyl, in particular methyl or ethyl.
It is possible and particularly advantageous to use the following compounds according to the invention:
These compounds can be prepared by, for example, the process described in German Patent Application P 33 33 455.2, in which the tert.-butyl or benzyl derivatives described in the application are converted in a known manner, by acid or alkaline hydrolysis or by hydrogenolysis catalyzed with noble metals, into the monocarboxylic acid derivatives. The N.sup..epsilon. -benzyloxycarbonyl protective group of the lysine derivatives is removed by hydrogenolysis catalyzed with noble metals. The compounds listed above can readily be converted with physiologically tolerated acids or bases (in the case of mono- or dicarboxylic acids) into the corresponding salts (for example hydrochlorides, maleates, fumarates etc.), and be used as salts according to the invention.
The compounds of the formula I are inhibitors of angiotensin converting enzyme (ACE) or are intermediates in the preparation of such inhibitors, and they can also be used for controlling high blood pressure of a variety of etiologies. Some of the compounds of the formula I and processes for their preparation are disclosed in, for example, U.S. Pat. No. 4,129,571, U.S. Pat. No. 4,374,829, European Patent A-79522, European Patent A-79022, European Patent A-49658, European Patent A-51301, U.S. Pat. No. 4,454,292, U.S. Pat. No. 4,374,847, European Patent A-72352, U.S. Pat. No. 4,350,704, European Patent A-50800, European Patent A-46953, U.S. Pat. No. 4,344,949, European Patent A-84164, U.S. Pat. No. 4,470,972, European Patent A-65301 and European Patent A-52991. New compounds of the formula I are prepared in an analogous manner.
Orally effective ACE inhibitors (some of the active compounds already mentioned above) are also advantageous, such as, for example, ramipril, enalapril(f), captopril(a), lisinopril(g), cilazapril(o), RHC 3659, CGS 13945, CGS 13928C(l), CGS 14824A(h), CI-906(j), zofenopril(e), fosenopril(p), alacepril, CI-925(k), pentopril(q), CV 3317(m), indolapril(h), YS 980(b), fentiapril(c), pivopril(d), perindopril(i), and others. Orally effective ACE inhibitors are described in, for example, Brunner et al., J. Cardiovasc. Pharmacol. 7 (Suppl. I) [1985] 2-11. ##STR7##
The ACE inhibitors which are disclosed in European Patent A-79022 and are of the formula III ##STR8## in which R denotes hydrogen, methyl, ethyl or benzyl, are preferred, in particular the compound of the formula III in which R denotes ethyl (ramipril).
Also preferred are the ACE inhibitors which are disclosed in European Patent A-84164 and are of the formula IV ##STR9## in which R.sup.4 denotes hydrogen, (C.sub.1 -C.sub.4)-alkyl or benzyl, in particular the compound of the formula IV in which R.sup.4 denotes ethyl.
Furthermore, preference is given to 1'-[N-(1-S-carboethoxy-3-phenylpropyl)-S-alanyl]-exo- or endo-spirobicyclo[2.2.2]octane-2,3'-pyrrolidin-5'-ylcarboxylic acid and isomers, and (S,S,S)-1-methyl-2-(1-carbethoxy-3-phenylpropyl)-2H-undecahydrocyclopenta[4.5]pyrrolo[1,2-a]pyrazine-3,8-dione.
The invention also relates to new compounds of the formula II ##STR10## A. in which I.
Suitable salts of the compounds of the formulae I and II are, depending on the acidic or basic nature of these compounds, alkali metal or alkaline earth metal salts or salts with physiologically tolerated amines, or salts with inorganic or organic acids such as, for example, HCl, HBr, H.sub.2 SO.sub.4, maleic acid, fumaric acid, tartaric acid and citric acid.
The capillary structure of the blood vessels in the brain differs from that in other regions of the body. The brain capillaries are surrounded by a layer of endothelial cells which are particularly closely linked together (by tight junctions). In addition, brain capillaries have very many fewer of the pores through which, in other blood capillaries, low molecular weight substances can penetrate into or emerge from the surrounding tissue. In this way, in the brain capillaries the property of lipid solubility has a very much greater importance for partition between blood and surrounding tissue than is the case for the remainder of the body.
Hence the preferred compounds of the formula II are those in which at least one of the radicals R, R.sup.1, R.sup.2 and R.sup.3 represents a lipophilic radical, such as a long-chain aliphatic, alicyclic-aliphatic, araliphatic or heteroaraliphatic radical, a sufficiently large alicyclic radical, or an appropriately substituted alicyclic, aromatic or heteroaromatic radical, or contains a radical of this type as a part-structure.
In this respect, particularly suitable compounds of the formula II are those in which
Additional compounds of the formula II which are suitable are those in which
In addition, preferred compounds of the formula II are those in which R.sup.2 and R.sup.3 are identical or different and denote propyl, isopropyl, n-butyl, isobutyl, sec.-butyl, n-pentyl, sec.-pentyl, isopentyl, neopentyl, n-hexyl, isohexyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclohexenyl, cycloheptenyl, menthyl, phenyl, .alpha.- or .beta.-naphthyl, 2-, 3- or 4-biphenylyl, phenethyl, 3-phenylpropyl, benzhydryl, .alpha.-methylbenzyl, .alpha.-methylenebenzyl, 2-, 3- or 4-phenylbenzyl, bibenzyl-.alpha.-yl, styryl, 1-indanyl or 9-fluorenyl, with phenyl, and phenyl as a part-structure of one of the said radicals, optionally being substituted as defined above under A.I.b)5., or one of the radicals R.sup.2 and R.sup.3 denotes hydrogen and the other is as defined above, or R.sup.2 represents benzyl, and R.sup.3 represents benzyl, hydrogen or one of the abovementioned definitions.
The invention also relates to a process for the preparation of a compound of the formula II, which comprises reacting together its fragments in a suitable solvent, where appropriate in the presence of a base and/or of a coupling aid, reducing, where appropriate, unsaturated compounds which have formed as intermediates, such as Schiff's bases, eliminating protective groups which have been introduced temporarily to protect reactive groups, esterifying, where appropriate, compounds of the formula II having one or more free carboxyl groups, and converting, where appropriate, the resulting compounds into their physiologically tolerated salts.
It is possible, for example, in the said manner to react compounds of the formula V with compounds of the formula VI. ##STR11##
The reaction of these compounds can be carried out, for example, in analogy to known peptide coupling methods in an organic solvent such as DMF, CH.sub.2 Cl.sub.2 or DMA in the presence of coupling aids such as carbodiimides (for example dicyclohexylcarbodiimide), diphenylphosphoryl azide, alkanephosphoric anhydrides, dialkylphosphinic anhydrides or N,N-succinimidyl carbonate, in a solvent such as CH.sub.3 CN. Amino groups in compounds of the formula V can be activated with tetraethyl diphosphite. The compounds of the formula VI can be converted into active esters (for example with 1-hydroxybenzotriazole), mixed anhydrides (for example with chloroformic esters), azides or carbodiimide derivatives and thus activated (cf. Schroder, Lubke, The Peptides, volume 1, New York 1965, pages 76-136). The reaction is preferably carried out between -20.degree. C. and the boiling point of the reaction mixture.
It is likewise possible to react compounds of the formula VII with compounds of the formula VIII with the formation of compounds of the formula II ##STR12## in which either Y.sup.1 represents amino and Y.sup.2 represents a leaving group, or Y.sup.1 represents a leaving group and Y.sup.2 represents amino. Examples of suitable leaving groups are Cl, Br, I, alkylsulfonyloxy or arylsulfonyloxy.
Alkylations of this type are expediently carried out in water or an organic solvent such as a lower aliphatic alcohol (such as ethanol), benzyl alcohol, acetonitrile, nitromethane or glycol ethers, at a temperature between -20.degree. C. and the boiling point of the reaction mixture, in the presence of a base such as an alkali metal hydroxide or an organic amine.
Furthermore, it is possible to condense compounds of the formula IX with compounds of the formula X ##STR13## in which either Q.sup.1 represents amino+hydrogen and Q.sup.2 represents oxo, or Q.sup.1 represents oxo and Q.sup.2 represents amino+hydrogen. The condensation is expediently carried out in water or an organic solvent such as a lower aliphatic alcohol, at a temperature between -20.degree. C. and the boiling point of the reaction mixture, in the presence of a reducing agent, such as NaBH.sub.3 CN, compounds of the formula I being obtained directly. However, it is also possible to reduce Schiff's bases or enamines which are produced as intermediates, where appropriate after previous isolation, with the formation of compounds of the formula II, for example by hydrogenation in the presence of a transition metal catalyst.
Finally, reaction of compounds of the formula IX (Q.sup.1 =H+NH.sub.2) with compounds of the formula XI, or their reaction with compounds of the formula XII and XIII, expediently in the presence of a base such as sodium alcoholate, in an organic solvent such as a lower alcohol, at a temperature between -10.degree. C. and the boiling point of the reaction mixture, also results in compounds of the formula II (n=2),
In the abovementioned formulae V-XIII, R-R.sup.5 and n are as defined in formula II. Protective groups temporarily introduced to protect reactive groups not involved in the reaction are eliminated in a manner known per se after the reaction is complete (cf. Schroder, Lubke, loc. cit., pages 1-75 and 246-270; Greene, "Protective Groups in Organic Synthesis", New York 1981).
The new compounds of the general formula I or II can also be prepared, for example, using methods of esterification familiar to the expert (see, for example, Buchler, Pearson, Survey of Organic Syntheses, vol. 1, New York 1970, pages 802-825; Houben-Weyl, Methoden der Organischen Chemie, (Methods of Organic Chemistry), volume E5, 1985, pages 656-773).
a) Reaction of a mono- or dicarboxylic acid of the general formula I or II in which at least one of the radicals R.sup.2 and R.sup.3 denotes hydrogen with an appropriate alcohol with acid catalysis (mineral acid or acid ion exchanger).
b) Alkylation of a mono- or dicarboxylic acid of the general formula I or II in which at least one of the radicals R.sup.2 and R.sup.3 denotes hydrogen with a compound R.sup.2 Z or R.sup.3 Z, in which Z denotes a leaving group which can be displaced nucleophilically (such as halogen, tosylate), in a polar protic or dipolar aprotic solvent, in the presence of a base such as an alkali metal hydroxide or alcoholate.
c) Reaction of a mono- or dicarboxylic acid of the general formula I or II in which at least one of the radicals R.sup.2 and R.sup.3 denotes hydrogen with a diazoalkene in an inert organic solvent such as CH.sub.2 Cl.sub.2.
The cognition adjuvant action of the compounds according to the invention has been tested in the inhibitory (passive) avoidance test (step-through model) in mice having a body weight of 20-25 g. A modified form of the test method described by J. KOPP, Z. BODANECKY and M. E. JARVIK has been described by J. BURES, O. BURESOVA and J. HUSTON in "Techniques and Basic Experiments for the Study of Brain and Behavior", Elsevier Scientific Publishers, Amsterdam (1983).
According to the statements in this literature, a substance is said to have cognition adjuvant activity when it is able to abolish the amnesia induced in the experimental animals by an electroconvulsive shock or the amnesia induced by scopolamine.
The experiments were carried out by modified test methods. The comparison compound used was the known cognition adjuvant 2-oxo-1-pyrrolidinylacetamide (piracetam). The marked superiority of the compounds according to the invention over the comparison substance was evident from the fact that the scopolamine-induced amnesia in the inhibitory avoidance test can be abolished with an oral MED (minimal effective dose) of 1.0-30 mg/kg. The comparison substance has an oral MED of about 500-1,000 mg/kg.
Most of the compounds according to the invention have only low toxicity.
By reason of their pharmacological properties, the compounds according to the invention are suitable not only for the treatment of high blood pressure but also for the treatment of cognitive dysfunctions of various etiologies, as occur with, for example, Alzheimer's disease or senile dementia.
Hence the invention also relates to the use of the compounds according to the invention for the treatment and prophylaxis of cognitive dysfunctions in patients with high blood pressure.
The invention furthermore embraces medicaments containing the said compounds, processes for their preparation and the use of the compounds according to the invention for the preparation of medicaments which can be used for the treatment and prophylaxis of the abovementioned diseases.
It is possible, in practicing the method according to the invention, to use the angiotensin converting enzyme inhibitors which are described above in mammals such as monkeys, dogs, cats, rats, humans etc.
The medicaments are prepared by processes which are known per se and familiar to those skilled in the art. The pharmacologically active compounds (=active compound) according to the invention are used as medicaments either as such or, preferably, combined with suitable pharmaceutical auxiliaries, in the form of tablets, coated tablets, capsules, suppositories, emulsions, suspensions or solutions, the content of active compound being up to about 95%, preferably between 10 and 75%.
The auxiliaries suitable for the desired medicament formulation are familiar to those skilled in the art by reason of their expert knowledge. Apart from solvents, gel-forming agents, suppository bases, tabletting auxiliaries and other active compound vehicles, it is possible to use, for example, antioxidants, dispersing agents, emulsifiers, antifoam agents, masking flavors, preservatives, solubilizers or colorants.
The active compounds can, for example, be administered orally, rectally or parenterally (for example intravenously or subcutaneously), oral administration being preferred.
For a form for oral use, the active compounds are mixed with the additives suitable for this purpose, such as excipients, stabilizers or inert diluents, and converted by the customary methods into suitable presentations such as tablets, coated tablets, hard gelatin capsules, aqueous, alcoholic or oily suspensions, or aqueous, alcoholic or oily solutions. Examples of inert vehicles which can be used are gum arabic, magnesia, magnesium carbonate, lactose, glucose or starch, in particular corn starch. This formulation can take the form of dry and of moist granules. Examples of suitable oily excipients or solvents are vegetable or animal oils such as sunflower oil or fishliver oil.
For subcutaneous or intravenous administration, the active compounds or their physiologically tolerated salts are converted into solutions, suspensions or emulsions, if appropriate with the substances customary for this purpose such as solubilizers, emulsifiers or other auxiliaries. Examples of suitable solvents are water, physiological saline solution or alcohols such as ethanol, propanol, glycerol, and in addition also sugar solutions such as glucose or mannitol solutions, as well as a mixture of the various solvents mentioned.
The following examples 1-6 indicate the forms used for the prophylaxis and treatment of cognitive dysfunctions by the method according to the invention. The compounds according to the invention can be converted into the appropriate use forms in analogy to the examples.
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|
Number |
Date |
Country |
| Parent |
226521 |
Aug 1988 |
|
| Parent |
29905 |
Mar 1987 |
|
Patent Grant
5231084
