JP2003500476A - Novel carboxylic acid derivatives having an aryl-substituted nitrogen heterocycle, their preparation and their use as endothelin receptor antagonists - Google Patents

Abstract

(57) [Summary] The present invention relates to a compound of the formula (I): Wherein the substituents represent those described herein, their preparation and their use as endothelin receptor antagonists.

Description

Detailed Description of the Invention

[0001]   The present invention relates to novel carboxylic acid derivatives, their production and use.

Endothelin is a peptide composed of 21 amino acids, which is synthesized and released by the vascular endothelium. Endothelin has three isomeric forms, E
Present in T-1, ET-2 and ET-3. In the following, "endothelin" or "ET" refers to one or all isomeric forms of endothelin. Endothelin is a potent vasoconstrictor and has a strong effect on vascular tone. This vasoconstriction is known to be due to endothelin binding to its receptor (Nature, 332, 411-415, 1988; FEBS Letters, 231, 440-444, 1988).
And Biochem. Biophys. Res. Commun., 154, 868-875, 1988).

Elevated or abnormal release of endothelin can lead to disease in the periphery,
It is responsible for persistent vasoconstriction in renal and cerebral blood vessels. As reported in the literature, endothelin is involved in a range of diseases. These include: hypertension, acute myocardial infarction, pulmonary hypertension, Raynaud's syndrome, cerebral vasospasm, stroke, benign prostatic hypertrophy, atherosclerosis, asthma and prostate cancer (J. Vas.
cular Med. Biology 2, 207 (1990), J. Am. Med. Association 264, 2868 (199
0), Nature 344, 114 (1990), N. Engl. J. Med. 322, 205 (1989), N. Engl. J
Med. 328, 1732 (1993), Nephron 66, 373 (1994), Stroke 25, 904 (1994),
Nature 365, 759 (1993), J. Mol. Cell. Cardiol. 27, A234 (1995); Cancer R
esearch 56, 663 (1996), Nature Medicine 1, 944, (1995)).

At least two endothelin receptor subtypes, the ET _A receptor and the ET _B receptor, are currently described in the literature (Nature 348, 730 (1990), Nature 348,
732, (1990)). Therefore, it should be possible to inhibit the binding of endothelin to one or both receptors, antagonize the physiological effects of endothelin, and thus provide a valuable medicament.

The manufacture and use of endothelin receptor antagonists has already been described in WO 95/26.
716, WO96 / 11914, WO97 / 38980, WO97 / 38982
, WO98 / 099953, WO98 / 27070, WO98 / 58916, WO
99/11629, DE 19748238.4, DE 19806438.1, D
E 1980944.3 and DE 19836044.4. These are compounds having a heteroaromatic ring each having at least one nitrogen atom, in which case the heteroaromatic ring has no phenyl substituents.
The challenge has arisen to provide alternative endothelin receptor antagonists with valuable pharmaceutical properties.

[0006]   The subject of the present invention is the formula I

[0007]

[Chemical 5]

[Wherein R ¹ is tetrazole or a group

[0009]

[Chemical 6]

[0010] (Wherein R represents the following:   a) group OR⁶, Then R⁶Represents the following:   Hydrogen, alkali metal cations, alkaline earth metal cations, physiologically accepted
Compatible organic ammonium ions such as tertiary C₁~ C_Four-Alkylammoni
Um or ammonium ion;   C_Three~ C₈-Cycloalkyl, C₁~ C₈-Alkyl, CH_Two-Phenyl, this
It may be substituted by one or more of the following groups: halogen, nitro
, Cyano, C₁~ C_Four-Alkyl, C₁~ C_Four-Halogenalkyl, hydroxy
, C₁~ C_Four-Alkoxy, mercapto, C₁~ C_Four-Alkylthio, amino,
NH (C₁~ C_Four-Alkyl), N (C₁~ C_Four-Alkyl)_Two;   C_Two~ C₆-Alkenyl group or C_Three~ C₆-Alkynyl groups, in which case these
The group may have 1 to 5 halogen atoms per se;   R⁶May further be a phenyl group, the phenyl group being 1 to 5 halogens.
It may have atoms and / or 1 to 3 groups: nitro, cyano, C ₁ ~ C_Four-Alkyl, C₁~ C_Four-Halogenalkyl, hydroxy, C₁~ C_Four -Alkoxy, mercapto, C₁~ C_Four-Alkylthio, amino, NH (C₁~
C_Four-Alkyl), N (C₁~ C_Four-Alkyl)_Two;   b) a 5-membered heteroaromatic ring linked via a nitrogen atom, for example pyrrolyl, pi
Razolyl, imidazolyl and triazolyl, wherein the ring has 1 to 2 halogen atoms,
Or 1-2 C₁~ C_Four-Alkyl or 1-2 C₁~ C_Four-Arukoki
May have a cis group   c) group

[0011]

[Chemical 7]

Where k is a value of 0, 1 and 2, p is a value of 1, 2, 3 and 4 and R ⁷ is C ₁ -C ₄ -alkyl, C ₃ C ₈ -cycloalkyl, C ₂ -C ₆ -alkenyl, C ₂ -C ₆ -alkynyl or phenyl, which phenyl is optionally substituted by one or more, for example 1 to 3, the following groups: Good: halogen, nitro, cyano, C ₁ -C ₄ -alkyl, C ₁ -C ₄ -halogenalkyl,
_Hydroxy, C 1 -C ₄ - _alkoxy, C 1 -C ₄ - alkylthio, mercapto, amino, NH _(C 1 ~C ₄ - _{alkyl), N (C 1 ~C 4} - _alkyl) 2) d) group

[0013]

[Chemical 8]

Wherein R ⁸ represents: C ₁ -C ₄ -alkyl, C ₂ -C ₆ -alkenyl, C ₂ -C ₆ -alkynyl,
C ₃ -C ₈ - cycloalkyl, in which, these _groups, C 1 -C ₄ - _alkoxy, C 1 -C ₄ - have a phenyl group as described alkylthio group and / or c) Phenyl, which may be substituted by 1 to 3 groups of the following: halogen,
Nitro, _cyano, C 1 -C ₄ - _alkyl, C 1 -C ₄ - haloalkyl, _hydroxy, C 1 -C ₄ - _alkoxy, C 1 -C ₄ - alkylthio, mercapto, amino, NH _(C 1 ~C ₄ - a carboxylic acid derivative of an _alkyl) 2))] - _{alkyl), N (C 1 ~C 4} .

[0015]   The remaining substituents represent:   R^TwoRepresents phenyl or phenoxy, benzyl, benzyloxy, where
, All aryl groups are 1 to 5 halogen atoms and / or 1 to 3 next groups
May have: hydroxy, mercapto, carboxy, nitro, cyano,
C₁~ C_Four-Alkyl, C₁~ C_Four-Halogenalkyl, C₁~ C_Four-Arukoki
Shi, C_Three~ C₆-Alkenyloxy, C_Three~ C₆-Alkynyloxy, C₁~ C _Four -Alkylthio, C₁~ C_Four-Halogenalkoxy, C₁~ C_Four-Alkyl
Lebonil, R⁹, C₁~ C_Four-Alkoxycarbonyl, (C₁~ C_Four-Alkyl
) NH carbonyl, (C₁~ C_Four-Alkyl)_TwoN carbonyl, C_Three~ C₈-A
Rukylcarbonylalkyl, amino, NH (C₁~ C_Four-Alkyl), N (C₁ ~ C_Four-Alkyl)_Two, Phenoxy or phenyl, in which case the aryl mentioned above
The group is again halogen, C₁~ C_Four-Alkyl, C₁~ C_Four-Halogen alk
Le, C₁~ C_Four-Alkoxy, C₁~ C_Four-Halogenalkoxy, dioxomethyi
Len, dioxoethylene, C₁~ C_Four1- to 3-substituted by alkylthio
May be;   Represents a 5- or 6-membered heteroaromatic ring, which has 1 to 3 nitrogen atoms and
And / or has one sulfur atom or oxygen atom, and the ring has 1 to 4 halo.
It may have a gen atom and / or 1 to 2 groups: C₁~ C_Four-A
Rukiru, C₁~ C_Four-Halogenalkyl, C₁~ C_Four-Alkoxy, C₁~ C_Four -Halogenalkoxy, C₁~ C_Four-Alkylthio, phenyl, phenoxy or
Is phenylcarbonyl, in which case the phenyl group is itself 1-5 halogen atoms.
And / or may have 1 to 3 of the following groups: C₁~ C_Four-Alkyl, C ₁ ~ C_Four-Halogenalkyl, C₁~ C_Four-Alkoxy, C₁~ C_Four-Halogen
Alkoxy and / or C₁~ C_Four-Alkylthio;   C_Three~ C₈-Cycloalkyl, which may have 1 to 3 of the following groups:
C₁~ C_Four-Alkyl, C₁~ C_Four-Halogenalkyl, C₁~ C_Four-Arukoki
Shi, C₁~ C_Four-Halogenalkoxy, C₁~ C_Four-Alkylthio.

[0016]   R^ThreeIs hydrogen;   C₁~ C₈-Alkyl, C_Three~ C₆-Alkenyl, C_Three~ C₆-Alkynylma
Or C_Three~ C₈-Cycloalkyl, in which case these groups are each
Mono- or polysubstituted: hydroxy, mercapto, carboxy
, Halogen, nitro, cyano, C₁~ C_Four-Alkoxy, C_Three~ C₆-Arkeni
Roxy, C_Three~ C₆-Alkynyloxy, C₁~ C_Four-Alkylthio, C₁~
C_Four-Halogenalkoxy, C₁~ C_Four-Alkylcarbonyl, C₁~ C_Four-A
Lucoxycarbonyl, (C₁~ C_Four-Alkyl) NH carbonyl, (C₁~ C_Four -Alkyl)_Two-N carbonyl, C_Three~ C₈-Alkylcarbonylalkyl, a
Mino, NH (C₁~ C_Four-Alkyl), N (C₁~ C_Four-Alkyl)_Two, Feno
Xy, phenyl or heteroaryl, which is 5 or 6 membered, 1-3
Having a nitrogen atom and / or one sulfur atom or an oxygen atom,
Wherein all the aryl and heteroaryl groups mentioned above are monosubstituted by
3 optionally substituted: halogen, nitro, cyano, C₁~ C_Four-Alkyl,
C₁~ C_Four-Halogenalkyl, C₁~ C_Four-Alkoxy, C₁~ C_Four-Halogen
Alkoxy, mercapto, carboxy, hydroxy, amino, R⁹, C₁~ C _Four -Alkoxycarbonyl, NH (C₁~ C_Four-Alkyl), N (C₁~ C_Four−
Alkyl)_Two, Dioxomethylene, dioxoethylene, C₁~ C_Four-Alkyl
O, phenyl or phenoxy;   Phenyl or naphthyl, each of which is based on one or more of the following groups:
Optionally substituted: halogen, nitro, cyano, hydroxy, amino, C₁~
C_Four-Alkyl, C₁~ C_Four-Halogenalkyl, C₁~ C_Four-Alkoxy, C ₁ ~ C_Four-Halogenalkoxy, phenoxy, C₁~ C_Four-Alkylthio, NH
(C₁~ C_Four-Alkyl), N (C₁~ C_Four-Alkyl)_TwoOr dioxomethy
Len or dioxoethylene;   A 5- or 6-membered heteroaromatic ring, which has 1 to 3 nitrogen atoms and / or
It has one sulfur atom or oxygen atom, and the ring has 1 to 4 halogen atoms.
And / or may have 1 to 2 of the following groups: C₁~ C_Four-Alkyl,
C₁~ C_Four-Halogenalkyl, C₁~ C_Four-Alkoxy, C₁~ C_Four-Halogen
Alkoxy, C₁~ C_Four-Alkylthio, phenyl, phenoxy or phenyl
Lecarbonyl, in which the phenyl group is itself 1-5 halogen atoms and / or
Or it may have 1 to 3 of the following groups: C₁~ C_Four-Alkyl, C₁~ C_Four -Halogenalkyl, C₁~ C_Four-Alkoxy, C₁~ C_Four− Halogen
Si and / or C₁~ C_Four-Alkylthio.

[0017]   R^FourAnd R⁵(May be the same or different):   Phenyl or naphthyl optionally substituted by one or more of the following groups
Le: halogen, nitro, cyano, hydroxy, C₁~ C_Four-Alkyl, C₁~ C _Four -Halogenalkyl, C₁~ C_Four-Alkoxy, C₁~ C_Four− Halogen alco
Xy, phenoxy, C₁~ C_Four-Alkylthio, amino, NH (C₁~ C_Four-A
Rukiru), N (C₁~ C_Four-Alkyl)_Two; Or   Direct bond at ortho position, methylene group, ethylene group or ethenylene group, oxygen source
Child or sulfur atom, or SO_TwoVia a-, NH- or N-alkyl- group
Bound to each other by phenyl or naphthyl; or   C_Three~ C₇-Cycloalkyl.

[0018]   X and Y (may be the same or different):   Nitrogen or methine; where X = Y = methine and Z = nitrogen.

Z is nitrogen or CR ¹⁰ .

Q is nitrogen or CR ¹¹ ; where X = Y = Z = nitrogen and Q = C
R ¹¹ .

R ⁹ is C ₁ -C ₄ -alkyl, C ₁ -C ₄ -alkylthio, C ₁ -C ₄ -alkoxy, which may have the following groups: hydroxy, carboxy, amino, NH _(C 1 ~C ₄ - _{alkyl), N (C 1 ~C 4} - _{alkyl) 2,} carboxamide or CON _(C 1 ~C ₄ - _alkyl) 2.

R ¹⁰ is hydrogen, halogen, hydroxy, NH ₂ , NH (C ₁ -C ₄ -alkyl), N (C ₁ -C ₄ -alkyl) ₂ , C ₁ -C ₄ -alkyl, C _2- . C ₄ - _alkenyl, C 2 _{~C 4} - _alkynyl, C 1 _{~C 4} - _{hydroxyalkyl, C} 1 ~
C ₄ - _{halogenalkyl,} C 1 -C ₄ - _alkoxy, C 1 -C ₄ - -haloalkoxy or _C 1 -C ₄ - alkylthio, or ^{CR 10,} together with ^{CR 11} 5-membered or 6-membered alkylene ring or It forms an alkenylene ring, which ring may be substituted by one or two C ₁ -C ₄ -alkyl groups and in each case one or more methylene groups are oxygen, sulfur, NH or -N (
C ₁ -C ₄ -alkyl) may be substituted; Phenyl optionally substituted 1 to 3 by the following groups: C ₁ -C ₄ -alkyl, C ₁ -C ₄ -halogenalkyl, C ₁ -C ₄ - _alkoxy, C 1 ~C ₄ - _-haloalkoxy, C 1 ~C ₄ - alkylthio.

[0023]   R¹¹Is hydrogen, hydroxy, NH_Two, NH (C₁~ C_Four-Alkyl), N (
C₁~ C_Four-Alkyl)_Two, Halogen, C₁~ C_Four-Alkyl, C_Two~ C_Four-A
Lucenil, C_Two~ C_Four-Alkynyl, C_Three~ C₆-Alkenyloxy, C₁~ C _Four -Alkylcarbonyl, C₁~ C_Four-Alkoxycarbonyl, C₁~ C_Four-Hi
Droxyalkyl, C₁~ C_Four-Halogenalkyl, C₁~ C_Four-Alkoxy,
C₁~ C_Four-Halogenalkoxy, -NH-O-C₁~ C_Four-Alkyl, C₁~
C_Four-Alkylthio, C_Three~ C₈-Cycloalkyl or CR¹¹Is R¹⁰In
CR as listed¹⁰Forms a 5- or 6-membered ring with;   Phenyl or phenoxy, which are 1 to 5 halogen atoms and / or
It may have 1 to 3 groups: hydroxy, mercapto, carboxy,
Nitro, cyano, C₁~ C_Four-Alkyl, C₁~ C_Four-Halogenalkyl, C₁ ~ C_Four-Alkoxy, C_Three~ C₆-Alkenyloxy, C_Three~ C₆-Alkynyl
Oxy, C₁~ C_Four-Alkylthio, C₁~ C_Four-Halogenalkoxy, C₁~
C_Four-Alkylcarbonyl, R⁹, C₁~ C_Four-Alkoxycarbonyl, (C₁ ~ C_Four-Alkyl) -NH carbonyl, (C₁~ C_Four-N alkyl)_TwoN carbo
Nil, C_Three~ C₈-Alkylcarbonylalkyl, amino, NH (C₁~ C_Four−
Alkyl), N (C₁~ C_Four-Alkyl)_Two, Phenoxy or phenyl, that
In this case, the aryl group is again halogen, C₁~ C_Four-Alkyl, C₁~ C _Four -Halogenalkyl, C₁~ C_Four-Alkoxy, C₁~ C_Four− Halogen alco
Xy, dioxomethylene, dioxoethylene, C₁~ C_Four-By alkylthio
1-substituted to 3-substituted;   5- or 6-membered heteroaromatic ring, which has 1 to 3 nitrogen atoms and / or
Has 1 sulfur atom or oxygen atom, and the ring has 1 to 4 halogen atoms.
It may have atoms and / or 1 to 2 groups: C₁~ C_Four-Archi
Le, C₁~ C_Four-Halogenalkyl, C₁~ C_Four-Alkoxy, C₁~ C_Four-C
Rogen alkoxy, C₁~ C_Four-Alkylthio, phenyl, phenoxy or phenyl
Phenylcarbonyl, in which the phenyl group is itself 1-5 halogen atoms and
/ Or may have 1 to 3 of the following groups: C₁~ C_Four-Alkyl, C₁~
C_Four-Halogenalkyl, C₁~ C_Four-Alkoxy, C₁~ C_Four− Halogen
Coxi and / or C₁~ C_Four-Alkylthio.

[0024]   A is sulfur or oxygen.

In this case and below, the following definitions apply: Alkali metals are, for example, lithium, sodium, potassium; Alkaline earth metals are, for example, calcium, magnesium, barium; organic ammonium ions are protonated amines, for example Ethanolamine, diethanolamine, ethylenediamine, diethylamine or piperazine; C ₃ -C ₈ -cycloalkyl is, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl; C ₁ -C ₄ -halogenalkyl is straight-chain or branched. It may be chain-like, for example, fluoromethyl, difluoromethyl, trifluoromethyl, chlorodifluoromethyl, dichlorofluoromethyl, trichloromethyl, 1-fluoroethyl, 2 Fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 2-chloro-2,2-difluoroethyl, 2,2-dichloro-2-fluoroethyl, 2,2,2-trichloroethyl Or pentafluoroethyl; C ₁ -C ₄ -halogenalkoxy may be straight-chain or branched,
For example, difluoromethoxy, trifluoromethoxy, chlorodifluoromethoxy, 1-fluoroethoxy, 2,2-difluoroethoxy, 1,1,2,2-tetrafluoroethoxy, 2,2,2-trifluoroethoxy, 2-chloro- 1,
1,2-trifluoroethoxy, 2-fluoroethoxy or pentafluoroethoxy; C ₁ -C ₄ -alkyl may be linear or branched, for example methyl, ethyl, 1-propyl, 2 -Propyl, 2-methyl-2-propyl, 2-
Methyl-1-propyl, 1-butyl or 2-butyl; _C 2 ~C ₄ - alkenyl may be linear or branched, such as ethenyl, 1-propen-3-yl, 1- Propen-2-yl, 1-propen-
1-yl, 2-methyl-1-propenyl, 1-butenyl or 2-butenyl; _C 2 -C ₄ - alkynyl may be linear or branched, such as ethynyl, 1-propyne - 1-yl, 1-propyn-3-yl, 1-butyne-4
-Yl or 2-butyn-4-yl; C ₁ -C ₄ -alkoxy may be linear or branched and are, for example, methoxy, ethoxy, propoxy, 1-methylethoxy, butoxy, 1-. Methylpropoxy, 2-methylpropoxy or 1,1-dimethylethoxy; C ₃ -C ₆ -alkenyloxy may be straight-chain or branched, for example allyloxy, 2-buten-1-yloxy or 3-buten-2-yloxy; _C 3 -C ₆ - alkynyloxy may be linear or branched, for example 2-propyn-1-yloxy, 2-butyn-1-yloxy or 3 −
Butyn-2-yloxy; C ₁ -C ₄ -alkylthio may be linear or branched and include, for example, methylthio, ethylthio, propylthio, 1-methylethylthio, butylthio, 1-methylpropylthio, 2-methylpropylthio or 1,1-dimethylethyl thio; _C 1 ~C ₄ - alkylcarbonyl may be linear or branched,
For example acetyl, ethylcarbonyl or 2-propylcarbonyl; C ₁ -C ₄ -alkoxycarbonyl may be linear or branched and are, for example, methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, i-propoxy. Carbonyl or n-butoxycarbonyl; Halogen is, for example, fluorine, chlorine, bromine, iodine.

Another subject of the invention is a compound (from which a compound of formula I can be released (
So-called prodrugs), for example amides of the acids contained in formula I.

Preference is given to prodrugs whose release proceeds under conditions such that they are predominant in specific body cavities, for example in the stomach, intestine, blood circulation, liver.

The compounds and intermediates for their preparation, such as II and IV, have one or more asymmetrically substituted carbon atoms. Such compounds are
It may exist as a pure enantiomer or a pure diastereomer, or as a mixture thereof. The use of enantiomerically pure compounds as active substances is advantageous.

A subject of the present invention is furthermore the use of the abovementioned carboxylic acid derivatives for the manufacture of a medicament, in particular for the production of inhibitors for the endothelin receptor.

The preparation of compounds (IV) of general formula IV in which Z is sulfur or oxygen is described in WO96
/ 11914.

[0031]

[Chemical 9]

The compounds of general formula III are known or can be synthesized, for example, by reduction of the corresponding carboxylic acids or their esters, or by other generally known methods.

The compounds of formula IV are obtained in the pure enantiomeric form by acid-catalyzed ether exchange, for example as described in WO 98/099953.

Furthermore, enantiomerically pure compounds of formula IV are obtained by carrying out a classical racemic resolution with a suitable enantiomerically pure base using a racemic or diastereomeric compound of formula IV. Suitable as such bases are, for example, 4-chlorophenylethylamine and the bases described in WO 96/11914.

The compounds according to the invention in which the substituents have the formulas given in the general formula I can be prepared, for example, from the carboxylic acid derivatives of the general formula IV in which the substituents have the general formula V
It can be produced by reacting with the compound of.

[0036]

[Chemical 10]

In formula V, R ¹² represents halogen or R ¹³ —SO ₂ —, where R ¹³ is C ₁ -C ₄ -alkyl, C ₁ -C ₄ -halogenalkyl or phenyl. Good. The reaction is preferably carried out in an inert solvent or diluent with the addition of a suitable base, ie a base which leads to the deprotonation of intermediate IV, in the temperature range from room temperature to the boiling point of the solvent.

When R ¹ is an ester, compounds having R ¹ ═COOH can be prepared by acidic, basic or catalytic separation of ester groups.

The compounds of type I with R ¹ = COOH are further deprotonated with intermediates IV, in which R ¹ represents COOH, by 2 equivalents of a suitable base and reacted with compounds of general formula V You can get it directly if you want to. Here too, the reaction is carried out in an inert solvent and in the temperature range from room temperature to the boiling point of the solvent.

Examples of such solvents or diluents are aliphatic, cycloaliphatic and aromatic hydrocarbons, which may optionally be chlorinated, for example hexane, cyclohexane, petroleum ether, ligroin, Benzene, toluene, xylene, methylene chloride, chloroform, carbon tetrachloride, ethyl chloride and trichlorethylene,
Ethers such as diisopropyl ether, dibutyl ether, methyl-t-
Butyl ether, propylene oxide, dioxane and tetrahydrofuran,
Nitriles such as acetonitrile and propionitrile, acid amides such as dimethylformamide, dimethylacetamide and N-methylpyrrolidone,
Sulfoxides and sulfones, such as dimethyl sulfoxide and sulfolane.

The compounds of formula V are known and are partly commercially available or can be prepared by generally known methods.

Alkali metal hydrides or alkaline earth metal hydrides as bases such as sodium hydride, potassium hydride or calcium hydride, carbonates such as alkali metal carbonates such as sodium carbonate or potassium carbonate, alkali metal hydroxides. Or alkaline earth metal hydroxides such as sodium or potassium hydroxide, organometallic compounds such as butyllithium or alkali metal amides such as lithium diisopropylamide.

The compounds of the formula I start from the corresponding carboxylic acids, ie compounds of the formula I in which R ¹ represents COOH, and the compounds are first prepared in a customary manner in the active form, for example the acid halogenide, the anhydride. Alternatively, it can also be prepared by converting to an imidazolide and then reacting it with the corresponding hydroxyl compound HOR ⁷ .
The reaction can be carried out in conventional solvents and often requires addition of a base, for example triethylamine, pyridine, imidazole or diazabicycloundecane. Both of these steps can easily be carried out, for example, by reacting a carboxylic acid with a hydroxyl compound in the presence of a substance which separates water, for example carbodiimide.

Furthermore, the compounds of the formula I can also be obtained from the corresponding salts of carboxylic acids, ie in which R ¹ is a group COOM (where M is an alkali metal cation or an equivalent of an alkaline earth metal cation). Can also be prepared by starting from a compound of formula I representing These salts can be reacted with numerous compounds of the formula R ¹ -D, where D represents a customary nucleophilic leaving group, for example halogen, such as chlorine, bromine, iodine, or Represents arylsulfonyl or alkylsulfonyl optionally substituted by halogen, alkyl or halogenalkyl, such as toluenesulfonyl and methylsulfonyl or other equivalent leaving groups. Compounds of formula R ¹ -D having a reactive substituent D are known or
Or easily obtained with general expertise. The reaction can be carried out in customary solvents and is preferably carried out with the addition of a base, which is considered above.

In some cases, application of commonly known protecting group techniques is required to prepare Compound I according to the present invention. For example, when R ⁶ = 4-hydroxyphenyl, the hydroxyl group can first be protected as a benzyl ether, which group is then separated at the appropriate stage in the reaction sequence.

Compounds of formula I in which R ¹ represents tetrazole may be prepared as described in WO 96/11914. Another possibility is, for example, Synthesis,
767 (1993); J. Org. Chem. 56, 2395 (1991).

[0047]   In terms of biological activity, carbohydrates of general formula I in which the substituents represent
Acid derivative as a pure enantiomer or as a pure diastereomer
Is also advantageous, or as a mixture thereof:   R^TwoIs phenyl or phenoxy, which may have 1 to 3 of the following groups
Good: halogen, C₁~ C_Four-Alkyl, C₁~ C_Four-Halogenalkyl, C₁ ~ C_Four-Alkoxy, C₁~ C_Four-Alkylthio, C₁~ C_Four− Halogen alco
Kish, C₁~ C_Four-Alkylcarbonyl, C₁~ C_Four-Alkoxycarbonyl,
(C₁~ C_Four-Alkyl) -NH carbonyl, (C₁~ C_Four-Alkyl)_TwoN
Lubonyl, NH (C₁~ C_Four-Alkyl), N (C₁~ C_Four-Alkyl)_Two;   5- or 6-membered heteroaromatic ring, which contains one nitrogen atom and / or one
May have a sulfur atom or an oxygen atom, and may have 1 to 2 of the following groups
Yes: halogen, C₁~ C_Four-Alkyl, C₁~ C_Four-Halogenalkyl, C₁~
C_Four-Alkoxy, C₁~ C_Four-Halogenalkoxy, C₁~ C_Four-Alkyl
O, phenyl, which itself may have 1 to 3 groups: halogen, C ₁ ~ C_Four-Alkyl, C₁~ C_Four-Halogenalkyl, C₁~ C_Four-Alkoxy
, C₁~ C_Four-Halogenalkoxy, C₁~ C_Four-Alkylthio;   C₅~ C₆-Cycloalkyl.

[0048]   R^ThreeIs hydrogen;   C₁~ C₈-Alkyl, C_Three~ C₆-Alkenyl, C_Three~ C₆-Alkynylma
Or C_Three~ C₈-Cycloalkyl, in which case these groups are each
Mono- or polysubstituted: hydroxy, halogen, C₁~ C_Four−
Alkoxy, C₁~ C_Four-Alkylthio, C₁~ C_Four-Halogenalkoxy, C ₁ ~ C_Four-Alkylcarbonyl, C₁~ C_Four-Alkoxycarbonyl, (C₁~
C_Four-Alkyl) -NH carbonyl, (C₁~ C_Four-Alkyl)_TwoN carbonyl
, Amino, NH (C₁~ C_Four-Alkyl), N (C₁~ C_Four-Alkyl)_Two, H
Enoxy or phenyl, heteroaryl, which are 5 or 6 members,
Has 1 to 3 nitrogen atoms and / or 1 sulfur atom or oxygen atom, and
In this case, the above aryl group and hetaryl group are substituted by the following 1 to 3 substituents.
May be included: halogen, C₁~ C_Four-Alkyl, C₁~ C_Four− Halogen
Kill, C₁~ C_Four-Alkoxy, C₁~ C_Four-Halogenalkoxy, R⁹, C₁ ~ C_Four-Alkoxycarbonyl, NH (C₁~ C_Four-Alkyl), N (C₁~ C _Four -Alkyl)_Two, Dioxomethylene, dioxoethylene, C₁~ C_Four-Archi
Lucio;   Phenyl or naphthyl, each of which is based on one or more of the following groups
May be substituted: halogen, C₁~ C_Four-Alkyl, C₁~ C_Four-Halogen
Alkyl, C₁~ C_Four-Alkoxy, C₁~ C_Four-Halogenalkoxy, C₁ ~ C_Four-Alkylthio, NH (C₁~ C_Four-Alkyl), N (C₁~ C_Four-Al
kill)_Two, Dioxomethylene or dioxoethylene;   Contains 1 to 3 nitrogen atoms and / or 1 sulfur atom or oxygen atom
A 5- or 6-membered heteroaromatic ring, which has 1 or 2 of the following groups
Good: C₁~ C_Four-Alkyl, C₁~ C_Four-Halogenalkyl, C₁~ C_Four−
Alkoxy, C₁~ C_Four-Halogenalkoxy, C₁~ C_Four-Alkylthio, fu
Phenyl, the phenyl is itself 1-5 halogen atoms and / or 1-3
May have a group of: C₁~ C_Four-Alkyl, C₁~ C_Four-Halogen alk
Le, C₁~ C_Four-Alkoxy, C₁~ C_Four-Halogenalkoxy, C₁~ C_Four−
Alkylthio.

R ⁴ and R ⁵ (may be the same or different): phenyl or naphthyl, which may be substituted by one or more of the following groups: halogen, C ₁ -C _4. - _alkyl, C 1 -C ₄ - _haloalkyl, C 1 -C ₄ - _alkoxy, C 1 -C ₄ - _-haloalkoxy, C 1 -C ₄ -
Alkylthio; or phenyl or naphthyl, which are directly linked in the ortho position, linked to one another via a methylene, ethylene or ethenylene group; or cyclohexyl.

[0050]   X and Y (may be the same or different):   Nitrogen or methine, where Z = nitrogen when X = Y = methine.

Z is nitrogen or CR ¹⁰ , with Q = CR ¹¹ when Z = nitrogen.

Q is nitrogen or CR ¹¹ .

R ⁹ is C ₁ -C ₄ -alkyl, C ₁ -C ₄ -alkylthio, C ₁ -C ₄ -alkoxy, which may have one of the following groups: hydroxy, carboxamide or CON _(C 1 ~C ₄ - _alkyl) 2.

R ¹⁰ is hydrogen, halogen, C ₁ -C ₄ -alkyl, C ₁ -C ₄ -halogenalkyl, C ₁ -C ₄ -alkoxy, C ₁ -C ₄ -halogenalkoxy or C ₁ -C ₄ -Alkylthio, or CR ¹⁰ together with CR ¹¹ form a 5- or 6-membered alkylene ring or alkenylene ring, which ring may be substituted by 1 or 2 methyl groups, and At this time, one or more methylene groups may be replaced by oxygen or sulfur.

R ¹¹ is hydrogen, NH (C ₁ -C ₄ -alkyl), N (C ₁ -C ₄ -alkyl) ₂ , C ₁ -C ₄ -alkyl, C ₁ -C ₄ -halogenalkyl, C _1- C ₄ -Alkoxy, C ₁ -C ₄ -halogenalkoxy, C ₁ -C ₄ -alkylthio, C ₅ -C ₆ -cycloalkyl, or CR ¹¹ together with CR ¹⁰ as described for R ^10. Form a 5 or 6 membered ring; phenyl or phenoxy, which may have 1 to 3 of the following groups:
_Halogen, C 1 _{~C 4} - _alkoxy, C 1 _{~C 4} - _alkylthio, C 1 _{~C 4} -
Halogenalkoxy, C ₁ -C ₄ -alkylcarbonyl, C ₁ -C ₄ -alkoxycarbonyl, (C ₁ -C ₄ -alkyl) NH carbonyl, (C ₁ -C ₄ -alkyl) ₂ N carbonyl, NH (C ₁ ˜C ₄ -alkyl), N (C ₁ -C ₄ -alkyl) ₂ ; a 5- or 6-membered heteroaromatic ring, which contains one nitrogen atom and / or 1
Has 1 sulfur atom or 1 oxygen atom and may have 1 or 2 groups: halogen, C ₁ -C ₄ -alkyl, C ₁ -C ₄ -halogenalkyl, C _1. -C ₄ - _alkoxy, C 1 -C ₄ - _-haloalkoxy, C 1 -C ₄ - alkylthio, phenyl, said phenyl may have one to three of the following groups themselves: _{halogen, C} 1 ~ C ₄ - _alkyl, C 1 _{~C 4} - _{halogenalkyl,} C 1 _{~C 4} - _alkoxy, C 1 _{~C 4} - _-haloalkoxy, C 1 _{~C 4} - alkylthio.

[0056]   A is sulfur or oxygen.

[0057]   Compounds of formula I in which the substituents represent: are pure enantiomers or
Are particularly advantageous both as pure diastereomers and as mixtures thereof.
Ru:   R^TwoIs phenyl or phenoxy, which has 1 to 3 groups of
Also good: halogen, C₁~ C_Four-Alkyl, C₁~ C_Four-Halogenalkyl, C ₁ ~ C_Four-Alkoxy, C₁~ C_Four-Alkylthio, C₁~ C_Four− Halogen
Coxy;   5- or 6-membered heteroaromatic ring, which contains one nitrogen atom and / or one
May have a sulfur atom or an oxygen atom, and may have 1 to 2 of the following groups
I:   Halogen, C₁~ C_Four-Alkyl, C₁~ C_Four-Halogenalkyl, C₁~ C _Four -Alkoxy, C₁~ C_Four-Halogenalkoxy, C₁~ C_Four-Alkylthio
;   C₅~ C₆-Cycloalkyl.

[0058]   R^ThreeIs hydrogen;   C₁~ C₈-Alkyl, or C_Three~ C₆-Cycloalkyl, in which case these
May be mono- to tri-substituted by the following groups respectively: hydroxy,
Halogen, C₁~ C_Four-Alkoxy, C₁~ C_Four-Alkylthio, C₁~ C_Four−
Halogenalkoxy, phenoxy, phenyl, heteroaryl, which have 5 members
Or 6 members, 1 nitrogen atom and / or 1 sulfur atom or oxygen
Having an atom, where the aryl and hetaryl groups above are
1 to 3 may be substituted by: halogen, C₁~ C_Four-Alkyl, C ₁ ~ C_Four-Halogenalkyl, C₁~ C_Four-Alkoxy, C₁~ C_Four-Halogen
Alkoxy, R⁹, Dioxomethylene, dioxoethylene, C₁~ C_Four-Archi
Lucio;   Phenyl or naphthyl, each substituted by one or more of the following groups
Optionally: halogen, C₁~ C_Four-Alkyl, C₁~ C_Four-Halogen alk
Le, C₁~ C_Four-Alkoxy, C₁~ C_Four-Halogenalkoxy, C₁~ C_Four−
Alkylthio, dioxomethylene or dioxoethylene;   A 5-membered heteroaromatic ring containing one sulfur or oxygen atom
, Optionally having 1 to 2 of the following groups: C₁~ C_Four-Alkyl, C₁~ C_Four−
Halogen alkyl, C₁~ C_Four-Alkoxy, C₁~ C_Four-Halogenalkoxy
, C₁~ C_Four-Alkylthio.

R ⁴ and R ⁵ (may be the same or different): phenyl or naphthyl, which may be substituted by one or more of the following groups: halogen, C ₁ -C ₄ — Alkyl, C ₁ -C ₄ -halogenalkyl, C ₁ -C ₄ -alkoxy, C ₁ -C ₄ -halogenalkoxy, C ₁ -C ₄ -alkylthio; or phenyl or naphthyl, which are directly bonded in the ortho position or methylene. It is linked via a group.

X and Y (may be the same or different): Nitrogen or methine; where Z is nitrogen when X = Y = methine; Z is nitrogen or CR ¹⁰ , Q is CR ¹¹ .

R ⁹ is C ₁ -C ₄ -alkyl, C ₁ -C ₄ -alkylthio, C ₁ -C ₄ -alkoxy, which may each have a hydroxyl group.

R ¹⁰ is hydrogen, halogen, methyl, trifluoromethyl, methoxy, or CR ¹⁰ together with CR ¹¹ forms a 5- or 6-membered alkylene ring, wherein the ring is 1 or 2 It may be substituted by a methyl group, and in that case one or more methylene groups may in each case be replaced by oxygen or sulfur.

[0063]   R¹¹Is hydrogen, C₁~ C_Four-Alkyl, C₁~ C_Four-Halogenalkyl, C ₁ ~ C_Four-Alkoxy, C₁~ C_Four-Halogenalkoxy, C₁~ C_Four-Archi
Lucio, C₅~ C₆-Cycloalkyl, or CR¹¹Is R¹⁰As described in
To CR¹⁰Form a 5- or 6-membered ring together with.

[0064]   A is sulfur or oxygen.

The compound of the present invention is effective for hypertension, pulmonary hypertension, myocardial infarction, angina, arrhythmia, acute / chronic renal dysfunction, chronic heart failure, renal failure, cerebrovascular spasm, cerebral ischemia, subarachnoid hemorrhage, migraine headache. , Asthma, atherosclerosis, endotoxic shock, exotoxin-induced organ dysfunction, endovascular coagulation, restenosis after angioplasty and bypass surgery, benign prostatic hyperplasia, erectile dysfunction, glaucoma, void New therapeutic potential for the treatment of renal dysfunction due to blood and poisoning, or hypertension, metastasis and growth of mesenchymal tumors, renal dysfunction induced by contrast agents, pancreatitis, gastrointestinal tumors provide.

Another subject of the invention is the combination of an endothelin receptor antagonist of formula I and an inhibitor of the renin-angiotensin system. Inhibitors of the renin-angiotensin system are renin inhibitors, angiotensin-II-antagonists and angiotensin-converting-enzyme (ACE) -inhibitors. Advantageously, the endothelin receptor antagonist of formula I is combined with an ACE-inhibitor.

Another subject of the invention is the endothelin receptor antagonists of formula I and β-
It is a combination with a blocker.

Another subject of the invention is the combination of an endothelin receptor antagonist of formula I with a diuretic.

Another subject of the invention is an endothelin receptor antagonist of formula I
It is a combination with a substance that blocks the action of EGF (vascular endothelial growth factor). Such substances are, for example, antibodies directed against VEGF or specific binding proteins or low molecular weight substances capable of specifically inhibiting VEGF release or receptor binding.

The combinations described above may be administered simultaneously or sequentially in a staggered manner. These can be used in a single pharmaceutical formulation or in separate formulations. The application form may be different, eg, the endothelin receptor antagonist may be administered orally and the VEGF inhibitor may be administered parenterally.

These combination preparations are particularly suitable for the treatment and prevention of hypertension and the diseases that follow, as well as for the treatment of heart failure.

[0072]   The good action of the compounds can be shown in the following tests.

Receptor Binding Assay Human ET _A or ET _B receptor expressing C cloned for binding assay
HO cells were used.

Membrane preparation CHO cells expressing ET _A or ET _B receptors were treated with DMEM NUT MI.
X F ₁₂ - medium (Gibco, No. 21331-020) fetal bovine serum in (PAA Laboratori
es GmbH, Linz, No. A15-022) 10%, Glutamine (Gibco No. 25030-024) 1
mM, penicillin 100E / ml and streptomycin (Gibco, Sigma No.
P-0781) Proliferated with 100 μg / ml. After 48 hours the cells were washed with PBS and incubated with 0.05% trypsin-containing PBS for 5 minutes at 37 ° C. It was then neutralized with medium and cells were harvested by centrifugation at 300 xg.

For the preparation of the membrane, the cells were adjusted to a concentration of 10 ⁸ cells / ml of buffer (50 mM Tris · HCl buffer, pH 7.4) and then disrupted by sonication (
Branson Sonifier 250, 40-70 seconds / constant / power 20).

Binding Assay For ET _A and ET _B receptor binding studies, membranes were incubated with incubation buffer (50 mM Tris-HCl, 5 mM MnCl ₂ at pH 7.
4, bacitracin 40 mg / ml and 0.2% BSA) at a concentration of 50 μg protein per test batch and at 25 ° C. 25 pM [125J] -E.
Incubation with T ₁ (ET _A -receptor test) or 25 pM [125J] -ET ₃ (ET _B -receptor test) in the presence and absence of test substance. Non-specific binding _ET 1 10 ^- we were determined using ⁷ M. Free radioligand and bound radioligand after 30 minutes were loaded onto the Skatron-Zel collector.
lsammler) (Skatron, Lier, Norwegen) and separated by filtration through a GF / B glass fiber filter (Whatman, UK) and the filter was ice-cooled.
Wash with is-HCl-buffer, 0.2% BSA, pH 7.4. Radioactivity collected on the filters was quantified using a Packard 2200CA liquid scintillation counter.

Functional vascular test for endothelin-receptor antagonists: 2 g of traction and 1 h of relaxation time at 37 ° C. and a pH value of 7.3-7.4 in Krebs-Henseleit solution in rabbit aortic sections. , Followed by first eliciting K ⁺ − contracture. After washing, a dose-effect curve of endothelin was generated up to the maximum value.

Potential endothelin-antagonist was applied for 15 minutes in another preparation of the same vessel prior to the start of the endothelin dose-effect curve. The effect of endothelin is calculated as% of K ⁺ − contracture. In the case of an effective endothelin-antagonist, this leads to a right shift of the endothelin dose-effect curve.

In vivo ET-antagonist testing: Male SD-rats weighing 250-300 g were anesthetized with amobarbital, ventilated, vagally transected and spinal cord removed. Catheter was inserted into the carotid artery and jugular vein.

Intravenous application of 1 μg / kg ET1 in control animals led to a clear increase in blood pressure, which persisted for a relatively long time.

Test animals were dosed i.p. with test compound 30 minutes prior to ET1 administration. v. Injected (1 ml /
kg). Changes in blood pressure in test animals were compared to changes in blood pressure in control animals to determine ET-antagonistic properties.

P. Of mixed ET _A and ET _B antagonists o. -Test: Male normotensive rats weighing 250-350 g (Sprague Dawley, Janvier
) Is pretreated orally with the test substance. After 80 minutes, the animals are anesthetized with urethane and catheterized into the carotid artery (for blood pressure measurement) as well as the jugular vein (application of big endothelin / endothelin 1).

After the stabilization step, big endothelin (20 μg / kg, application volume 0.5 m
1 / kg) or ET1 (0.3 μg / kg, application volume 0.5 ml / kg) was administered intravenously. Blood pressure and heart rate were recorded continuously for 30 minutes. Obvious and long-lasting changes in blood pressure are calculated as the plane under the curve (AUC). To measure the antagonism of the test substance, the AUC of the substance-treated animal is compared with the AUC of the control animal.

The compounds according to the invention can be administered orally or parenterally (subcutaneously, intravenously, intramuscularly, intraperitoneally) by customary methods. Apply using the steam or spray to the nose
It can also be done by the pharyngeal cavity.

The dosage depends on the age, condition and weight of the patient and on the method of application. Usually,
The daily dose of the active substance is about 0.5 to 50 mg / kg body weight for oral administration, and about 0.1 to 10 mg / kg body weight for parenteral administration.

The novel compounds are in the customary pharmaceutical application forms, solid or liquid, for example tablets, coated tablets, capsules, powders, granules, dragees, suppositories, solutions, ointments, creams or sprays. Can be applied as These are manufactured by an ordinary method. In this case, the active substances are customary pharmaceutical additives such as tablet binders, fillers, preservatives, tablet disintegrants, flow control agents, softeners, wetting agents, dispersants, emulsifiers, solvents, retarders, antioxidants and And / or can be processed using a blast gas (
H. Sucker et al .: Pharmazeutische Technologie, Thieme-Verlag, Stuttgart,
See 1991). The application form thus obtained usually contains no active substance.
． It is contained in an amount of 1 to 90% by mass.

Synthetic Examples: Example 1: 4-Methyl-2-methylsulfanyl-6-phenyl-pyrimidine 4-Methyl-6-phenyl-pyrimidine-2-thiol (300 mg, 1 at 92% purity) in methanol (15 ml). .37 mmol, DJ Brown et al., Au
st. J. Chem. 1984, 37, 155) to a solution of 1 molar caustic soda solution (4.10 ml; 4.10 mmol) and iodomethane (86 μl;
194 mg; 1.37 mmol) were added sequentially. The batch was stirred at room temperature for 16 hours, then diluted with water (50 ml) and acidified with hydrochloric acid. The mixture was extracted with ethyl acetate (3 times), the combined organic phases were dried over magnesium sulfate and the solvent was removed under vacuum. 290 mg of the desired pyrimidine (1.24 mmol,
Yield 91%, lt. (93% purity by HPLC).

Example 2: 2-Methanesulfonyl-4-methyl-6-phenyl-pyrimidine 4-methyl-2-methylsulfanyl-6-phenyl-pyrimidine (278 mg, purity 93) in methanol (10 ml) and water (10 ml). % in a solution of 1.19 mmol) under ice-cooling ^{Oxone (R) (Aldrich; 973mg} , 1.58 mmol) and 4 molar sodium hydroxide solution (0.85 ml; 3.33 mmol)
Was added simultaneously and the pH value was always maintained at pH 2-3. It was then stirred at room temperature for 16 hours and then interrupted by diluting with water (75 ml). The mixture was extracted with ether (2 times) and then ethyl acetate (1 time), the combined organic phases were dried over magnesium sulphate and the solvent was removed under vacuum. This gave 290 mg (1.11 mmol, 93% yield, 95% purity by lt.HPLC) of the desired sulfonylpyrimidine. Further use without further purification.

Example 3: 3-Ethoxy-2- (4-methyl-6-phenyl-pyrimidin-2-yloxy) -3,3-diphenyl-propionic acid (I-180) 2 in anhydrous dimethylformamide (10 ml). -Methanesulfonyl-4-methyl-6-phenyl-pyrimidine (145 mg; 0.55 mmol at 95% purity)
To a solution of 50% sodium hydride (72 mg, 1.51 mmol) and then 3-ethoxy-2-hydroxy-3,3-diphenylpropionic acid (150 mg, 0.50 mmol; WO96 / 11914) in dimethylformamide. Solution) and stirred at room temperature. After 3 hours, the sulfonylpyrimidine was completely consumed, but the hydroxy acid was not yet completely reacted, so 30 mg of the sulfonylpyrimidine was added again. After stirring for another hour at room temperature, the reaction was almost complete and was stopped by the addition of water. After acidifying with hydrochloric acid, it was extracted with ether (3 times). The ethereal extracts were extracted with a 1 molar aqueous solution of caustic, the alkaline aqueous extracts were combined, re-acidified and extracted three times with ether. The ethereal extract obtained from this was dried over magnesium sulphate and concentrated by evaporation. The residual crude product was purified by flash chromatography on silica gel and isolated by freeze-drying. 47 mg (0.09 mmol; yield 19%) of the target compound was obtained.

¹ H-NMR (200 MHz, CDCl ₃ ): 7.9 to 8.1 (m, 2H);
7.1-7.7 (m, 14H); 6.5 (s, 1H); 3.3-3.7 (m, 2)
H); 2.5 (s, 3H); 1.2 (t, 3H).

ESI-MS: M ⁺ = 454.

Example 4: 3-Methoxy-2- (4-methyl-6-phenyl-pyrimidin-2-yloxy) -3,3-diphenyl-propionic acid (I-58) ¹ H-NMR (200 MHz, CDCl ₃ ): 7.9 to 8.1 (m, 2H);
7.2-7.7 (m, 14H); 6.4 (s, 1H); 3.3 (s, 3H); 2
． 5 (s, 3H).

ESI-MS: M ⁺ = 440.

Example 5: 2-Methylsulfanyl-6-phenyl-pyrimidin-4-ol 2-mercapto-6-phenyl-pyrimidine-4 in methanol (10 ml).
-Ol (1.06 g; 5.18 mmol; HI Skulnick et al., J. Med. C)
hem. 1986, 29 (8), 1499) to a solution of 1 molar caustic soda solution (15.0 ml; 15.0 mmol) and iodomethane (0.33 ml;
735 mg; 5.18 mmol) were added sequentially. The batch was stirred at room temperature for 30 minutes, then diluted with water (100 ml) and acidified with hydrochloric acid. The mixture is extracted with ethyl acetate (3 times), the combined organic phases are dried over magnesium sulphate,
And the solvent was removed under vacuum. This yielded 750 mg (3.44 mmol, 66% yield) of the desired product.

Example 6: 4-Chloro-2-methylsulfanyl-6-phenyl-pyrimidine 2-Methylsulfanyl-6-phenyl-pyrimidin-4-ol (854 mg; 3.91) in phosphorus oxychloride (10.0 ml). (Mmol) solution was heated to 80 ° C under stirring and stirred at this temperature for 2 hours. After cooling, phosphorus oxychloride was removed under vacuum. The residue was taken up in ethyl acetate and washed with water (3 times). The organic phase was dried over magnesium sulfate and the solvent was distilled off under vacuum. After distilling off again with toluene, the desired chloropyrimidine was obtained with a purity of 95% (950 m).
g; 3,81 mol; yield 97%).

Example 7: 4-Methoxy-2-methylsulfanyl-6-phenyl-pyrimidine 4-chloro-2-methylsulfanyl-6- in anhydrous methanol (15 ml).
A mixture of phenyl-pyrimidines (950 mg, 3.81 mmol at 95% purity) was added to a 30% solution of methanolic sodium methanolate (4.50%) under a nitrogen atmosphere.
ml) was added. The resulting mixture is heated to boiling under reflux and at this temperature 9
Stir for 0 minutes. Then, the mixture was further stirred at room temperature for 16 hours, and the solvent was distilled off. The residue was added to water and extracted with ethyl acetate (3 times). The organic phase was dried over magnesium sulphate and evaporated. The desired compound was obtained in the form of yellow crystals (854 mg; 3.60 mmol; 94%).

Example 8: 2-Methanesulfonyl-4-methoxy-6-phenyl-pyrimidine 4-Methoxy-2-methylsulfanyl-6-phenyl-pyrimidine (854 mg; 3.85 ml) in methanol (15 ml) and water (15 ml). Oxone ^(R) (Aldrich; 3.32 g; 5.40 mmol) and 4 mol caustic soda solution (2.50 ml; 10.0 mmol) were simultaneously added to a solution of 60 mmol) under ice cooling to obtain a pH value. Was always maintained at pH 2-3. It was then post-stirred for 16 hours at room temperature and then interrupted by dilution with water (75 ml). The mixture is extracted with ethyl acetate (twice); the combined organic phases are dried over magnesium sulphate and freed from the solvent under vacuum. 928 mg of the desired sulfonylpyrimidine (3.17 mmol,
Yield 88%, lt. 90% purity by HPLC). Further use without further purification.

Example 9: 3-Methoxy-2- (4-methoxy-6-phenyl-pyrimidin-2-yloxy) -3,3-diphenyl-propionic acid (I-64) 3 in anhydrous dimethylformamide (10 ml). -Methoxy-2-hydroxy-
3,3-diphenylpropionic acid (200 mg; 0.73 mmol; WO96 /
Solution of 11914) under ice-cooling and nitrogen atmosphere with stirring at 50%.
Sodium hydride (106 mg; 2.20 mmol) was added. After 10 minutes 2-methanesulfonyl-4-methoxy-6-phenyl-pyrimidine (320 mg
1.09 mmol at 90% purity) was dissolved in a small amount of dimethylformamide and added. The cooling bath was removed and post-stirred at room temperature for 16 hours. It was then interrupted by the careful addition of water, acidified with hydrochloric acid and extracted with ether (3 times). The ethereal extracts were extracted with 1 molar caustic solution, the alkaline aqueous extracts were combined, re-acidified and extracted three times with ether. The ethereal extract obtained from this is dried over magnesium sulphate and, for example, added with hexane and evaporated to a low temperature. 317 mg of the target compound (0.
67 mmol, yield 92%) was obtained.

¹ H-NMR (200 MHz, CDCl ₃ ): 7.9 to 8.1 (m, 2H);
7.2-7.6 (m, 13H); 6.8 (s, 1H); 6.3 (s, 1H); 3
． 9 (s, 3H); 3.3 (s, 3H).

[0100]   Melting point 110-115 [deg.] C.

Example 10: 3-Ethoxy-2- (4-methoxy-6-phenyl-pyrimidin-2-yloxy) -3,3-diphenyl-propionic acid (I-95) Example 11: 3-Methoxy-2- [4-Methoxy-6- (4-trifluoromethyl-phenyl) -pyrimidin-2-yloxy] -3,3-diphenylpropionic acid (I-6
) ¹ H-NMR (200 MHz, d ₆ -DMSO): 8.3 (d, 2H);
8 (d, 2H); 7.4 (map t, 4H); 7.1 (s, 1H);
0-7.3 (m, 6H); 6.3 (s, 1H); 3.9 (s, 3H); 3.4 (
s, 3H).

ESI-MS: M ⁺ = 524.

Example 12: 3-Ethoxy-2- [4-methoxy-6- (4-trifluoromethyl-phenyl) -pyrimidin-2-yloxy] -3,3-diphenylpropionic acid (I-1
59) ¹ H-NMR (200 MHz, CDCl ₃ ): 8.0 (d, 2H); 7.7 (
d, 2H); 7.6 (m, 2H); 7.2-7.5 (m, 8H); 6.8 (s,
1H); 6.4 (s, 1H); 4.0 (s, 3H); 3.5 (mc, 2H); 1
． 3 (t, 3H).

ESI-MS: M ⁺ = 538.

Example 13: 2- [4- (4-isopropyl-phenyl) -6-methoxy-pyrimidine-2-
Iloxy] -3-methoxy-3,3-diphenylpropionic acid (I-87) ¹ H-NMR (200 MHz, CDCl ₃ ): 7.9 (d, 2H); 7.6 (
m app d, 2H); 7.2-7.4 (m, 10H); 6.8 (s, 1H)
6.4 (s, 1H); 3.9 (s, 3H); 3.3 (s, 3H); 2.9 (s
ept, 1H); 1.3 (d, 6H).

ESI-MS: M ⁺ = 498.

Example 14: 2,4-Dichloro-6-ethyl- [1,3,5] -triazine A solution of cyanuric chloride (23.1 g; 184 mmol) in anhydrous toluene (200 ml) was cooled with ice and nitrogen. Within 20 minutes under atmosphere, a 2 molar solution of ethylmagnesium chloride in tetrahydrofuran (100 ml; 200 mmol) was added dropwise. At that time, the temperature gradually rose to 15 ° C. 2 more at room temperature after the addition is complete
After stirring for a time. Very carefully (!) Water (4) to the mixture to stop the reaction.
0 ml) and filtered off after addition of solid magnesium sulphate (40 g). The filtrate was concentrated by evaporation and the remaining residue was distilled off with hexane. After the hexane was distilled off, the residue was purified by flash chromatography using silica gel. This gave 8.80 g (49.4 mmol; 40% yield) of an oil.

Example 15: 2-Chloro-4-ethyl-6-phenyl- [1,3,5] -triazine 2,4-Dichloro-6-ethyl- [1 in anhydrous dichloromethane (50 ml).
, 3,5] -Triazine (1.78 g; 10.0 mmol) was cooled to −10 ° C. to −20 ° C. under a nitrogen atmosphere and a 2 molar solution of phenylmagnesium chloride in tetrahydrofuran (5 min. 5.50 ml; 11.0 mmol) was added. The temperature was raised to room temperature, and the mixture was further stirred at room temperature for 1 hour. Water (3 ml
The reaction was stopped by the careful addition of). Then, 3 g of solid magnesium sulfate was further added. After filtering off the undissolved components, the solvent was distilled off, and the remaining oily substance was purified by chromatography. This gave 1.35 g of an oil. Despite the chromatographic treatment, its purity was lt. It was only 66% by HPLC (4.07 mmol; yield 41%).

Example 16: 3-Ethoxy-2-hydroxy-3,3-diphenylpropionic acid benzyl ester 3,3-Diphenyl-oxirane-2-carboxylic acid benzyl ester (10.0 g; purity) in anhydrous ether (100 ml). Absolute ethanol (10.0 ml) and boron trifluoride etherate (3-4 drops) were added sequentially to a solution of 92% at 30.3 mmol) under ice cooling and nitrogen atmosphere. The cooling bath was removed and stirred at room temperature for a further 2 hours. After washing with saturated sodium hydrogen carbonate solution and water, it is dried over magnesium sulphate and evaporated down. The residue was purified by crystallization from ether / n-hexane. Pure hydroxy ester 6.60 g (17
． 5 mmol; yield 58%).

¹ H-NMR (200 MHz, CDCl ₃ ): 7.2-7.5 (m, 15H)
5.2 (d, 1H); 5.0 (s, 2H); 3.4 (m, 1H); 3.2 (m
, 1H); 3.0 (d, 1H); 1.1 (t, 3H).

Example 17: 3-Ethoxy-2- (4-ethyl-6-phenyl- [1,3,5] -triazin-2-yloxy) -3,3-diphenylpropionic acid benzyl ester (I-
17) 3-Ethoxy-2-hydroxy-in anhydrous dimethylformamide (30 ml)
3,3-Diphenylpropionic acid-benzyl ester (376 mg; 1.00 mmol) and 2-chloro-4-ethyl-6-phenyl- [1,3,5] -triazine (497 mg; 1.50 at 66% purity). To a solution of potassium carbonate (
276 mg; 2.00 mmol) and stirred at room temperature for 16 hours. The mixture was diluted with water (150 ml), acidified with citric acid and extracted with ether (2x). The combined ethereal extracts were dried over magnesium sulfate and the solvent was removed under vacuum. The oily residue was purified by flash chromatography. 431 mg (0.77 mmol, 77% yield) of pure target compound were obtained.

Example 18: 3-Ethoxy-2- (4-ethyl-6-phenyl- [1,3,5] -triazin-2-yloxy) -3,3-diphenylpropionic acid (I-102) ethyl acetate A solution of 3-ethoxy-2- (4-ethyl-6-phenyl- [1,3,5] -triazin-1-yloxy) -3,3-diphenylpropionic acid benzyl ester in (60 ml) (430 mg; 0 (0.77 mmol) under protective gas with palladium / activated carbon-hydrogenation catalyst and subsequently stirred under hydrogen atmosphere at room temperature for 3 days. Then the catalyst was filtered off and concentrated by evaporation. 187 mg of pure carboxylic acid by crystallizing the oily residue from n-hexane (0.
40 mmol; yield 52%).

¹ H-NMR (200 MHz, CDCl ₃ ): 8.4 (d, 2H); 7.2-
7.7 (m, 13H); 6.5 (s, 1H); 3.5-3.7 (m, 1H); 3
． 25-3.45 (m, 1H); 2.9 (q, 2H); 1.2-1.4 (m, 6
H).

ESI-MS: M ⁺ = 469.

Similarly prepared was the following: Example 19: 2- (4-Ethyl-6-phenyl- [1,3,5] -triazin-2-yloxy) -3-methoxy-3,3-diphenyl Propionic acid (I-109) ¹ H-NMR (200 MHz, CDCl ₃ ): 8.5 (d, 2H); 7.2-
7.7 (m, 13H); 6.5 (s, 1H); 3.3 (s, 3H); 2.9 (q
, 2H); 1.3 (t, 3H).

ESI-MS: M ⁺ = 455.

Example 20: 2- [4-Ethyl-6- (4-methoxy-phenyl)-[1,3,5] -triazin-2-yloxy] -3-methoxy-3,3-diphenylpropionic acid ( I
-23) ¹ H-NMR (200 MHz, CDCl ₃ ): 8.4 (d, 2H); 7.5-
7.6 (m, 2H); 7.2-7.5 (m, 8H); 7.0 (d, 2H);
4 (s, 1H); 3.9 (s, 3H); 3.3 (s, 3H); 2.9 (q, 2H)
); 1.3 (t, 3H).

ESI-MS: M ⁺ = 485.

Example 21: 3-Ethoxy-2- [4-ethyl-6- (4-methoxy-phenyl)-[1,3
, 5] -Triazin-2-yloxy] -3,3-diphenylpropionic acid (I
-147) ¹ H-NMR (200 MHz, CDCl ₃ ): 8.4 (d, 2H); 7.5-
7.6 (m, 2H); 7.2-7.5 (m, 8H); 7.0 (d, 2H);
5 (s, 1H); 3.9 (s, 3H); 3.3 to 3.7 (m, 2H); 2.8 (
q, 2H); 1.35 (t, 3H); 1.25 (t, 3H).

ESI-MS: M ⁺ = 499.

Example 22: 2- [4,6-Diphenyl)-[1,3,5] -triazin-2-yloxy-
3-Methoxy-3,3-diphenyl-propionic acid (I-29) ¹ H-NMR (200 MHz, CDCl ₃ ): 8.6 (d, 4H); 7.2-
7.7 (m, 16H); 6.5 (s, 1H); 3.3 (s, 3H).

ESI-MS: M ⁺ = 503.

Example 23: 2- [4,6-Diphenyl)-[1,3,5] -triazin-2-yloxy]
3-ethoxy-3,3 - propionic acid _{^{(I-41) 1 H-}} NMR (200MHz, CDCl 3): 8.6 (d, 4H); 7.2~
7.7 (m, 16H); 6.6 (s, 1H); 3.3-3.7 (s, 2H); 1
． 3 (t, 3H).

ESI-MS: M ⁺ = 517.

In a similar manner or as explained in the general description, the compounds listed in Table 1 can be prepared.

[0126]

[Table 1]

[0127]

[Table 2]

[0128]

[Table 3]

[0129]

[Table 4]

[0130]

[Table 5]

[0131]

[Table 6]

[0132]

[Table 7]

[0133]

[Table 8]

[0134]

[Table 9]

Example 24: Receptor binding data was determined for the compounds described below, as described in the binding studies above.

[0136]   The results are shown in Table 2.

[0137]

[Table 10]

─────────────────────────────────────────────────── ─── Continuation of front page (51) Int.Cl. ⁷ Identification code FI theme code (reference) A61K 45/00 A61K 45/00 A61P 9/00 A61P 9/00 9/04 9/04 9/10 9 / 10 9/12 9/12 11/06 11/06 13/08 13/08 35/00 35/00 C07D 213/64 C07D 213/64 213/68 213/68 237/14 237/14 251/14 251 / 14 253/06 253/06 F (81) Designated country EP (AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR, IE, IT, LU, MC, NL, PT, SE), OA (BF, BJ, CF, CG, CI, CM, GA, GN, GW, ML, MR, NE, SN, TD, TG), AP (GH, GM, KE, LS, MW, MZ , SD, SL, SZ, TZ, UG, ZW), EA (AM, AZ, BY, KG, KZ, M D, RU, TJ, TM), AE, AG, AL, AM, AT, AU, AZ, BA, BB, BG, BR, BY, CA, CH, CN, CR, CU, CZ, DE, DK, DM, DZ, EE, ES, FI, GB, GD, GE, GH, GM, HR, HU, ID, IL, IN, IS, JP, KE, KG, KP, KR, KZ, LC, LK, LR , LS, LT, LU, LV, MA, MD, MG, MK, MN, MW, MX, MZ, NO, NZ, PL, PT, RO, RU, SD, SE, SG, SI, SK, SL, TJ, TM, TR, TT, TZ, UA, UG, US, UZ, VN, YU, ZA, ZW F terms (reference) 4C055 AA01 BA03 BA07 BA13 BA42 BB08 CA01 DA06 4C084 AA19 MA02 MA52 MA55 MA56 ZA361 ZA421 ZA591 ZA811 ZB 4C086 AA01 AA03 BC17 BC41 BC42 BC64 GA07 MA02 MA04 MA52 MA55 MA56 NA14 ZA36 ZA42 ZA59 ZA8 1 ZB26

Claims (8)

[Claims] 1. Formula I     [Chemical 1] [In the formula,   R¹Is a tetrazole or group     [Chemical 2] (Wherein R represents the following:   a) group OR⁶, Then R⁶Represents the following:   Hydrogen, alkali metal cations, alkaline earth metal cations, physiologically accepted
Compatible organic ammonium ions such as tertiary C₁~ C_Four-Alkylammoni
Um or ammonium ion;   C_Three~ C₈-Cycloalkyl, C₁~ C₈-Alkyl, CH_Two-Phenyl, said
Phenyl may be substituted by one or more of the following groups: halogen,
Nitro, cyano, C₁~ C_Four-Alkyl, C₁~ C_Four-Halogenalkyl, hydr
Roxy, C₁~ C_Four-Alkoxy, mercapto, C₁~ C_Four-Alkylthio, a
Mino, NH (C₁~ C_Four-Alkyl), N (C₁~ C_Four-Alkyl)_Two;   C_Two~ C₆-Alkenyl group or C_Three~ C₆-Alkynyl groups, in which case these
The group may have 1 to 5 halogen atoms per se;   R⁶May further be a phenyl group, the phenyl group being 1 to 5 halogens.
It may have atoms and / or 1 to 3 groups: nitro, cyano, C ₁ ~ C_Four-Alkyl, C₁~ C_Four-Halogenalkyl, hydroxy, C₁~ C_Four -Alkoxy, mercapto, C₁~ C_Four-Alkylthio, amino, NH (C₁~
C_Four-Alkyl), N (C₁~ C_Four-Alkyl)_Two;   b) a 5-membered heteroaromatic ring linked via a nitrogen atom, for example pyrrolyl, pi
Razolyl, imidazolyl and triazolyl, wherein the ring has 1 to 2 halogen atoms,
Or 1-2 C₁~ C_Four-Alkyl or 1-2 C₁~ C_Four-Arukoki
May have a cis group   c) group     [Chemical 3] Where k is a value of 0, 1 and 2 and p is a value of 1, 2, 3 and 4.
And   R⁷Is C₁~ C_Four-Alkyl, C_Three~ C₈-Cycloalkyl, C_Three~ C₆-A
Lucenil, C_Three~ C₆-Alkynyl or phenyl, said phenyl being one or
It may be substituted by a plurality, for example 1 to 3, of the following groups: halogen, di
Toro, cyano, C₁~ C_Four-Alkyl, C₁~ C_Four-Halogenalkyl, hydro
Kish, C₁~ C_Four-Alkoxy, C₁~ C_Four-Alkylthio, mercapto, ami
No, NH (C₁~ C_Four-Alkyl), N (C₁~ C_Four-Alkyl)_Two),   d) group     [Chemical 4] (R in the formula⁸Represents the following:   C₁~ C_Four-Alkyl, C_Two~ C₆-Alkenyl, C_Two~ C₆-Alkynyl,
C_Three~ C₈-Cycloalkyl, in which case these radicals are C₁~ C_Four-Alkoxy
Base, C₁~ C_Four-Alkylthio groups and / or phenyl as described under c)
May have a group;   Phenyl, which may be substituted by 1 to 3 of the following groups: halogen,
Nitro, cyano, C₁~ C_Four-Alkyl, C₁~ C_Four-Halogenalkyl, hydr
Roxy, C₁~ C_Four-Alkoxy, C₁~ C_Four-Alkylthio, mercapto, a
Mino, NH (C₁~ C_Four-Alkyl), N (C₁~ C_Four-Alkyl)_Two)) Table
Then   R^TwoIs benzyl, benzyloxy, phenyl or phenoxy, these are
Each may be substituted; or   A 5- or 6-membered heteroaromatic ring, which has 1 to 3 nitrogen atoms and / or
It has one sulfur atom or oxygen atom and may be substituted respectively.
; Or C_Three~ C₈-Cycloalkyl, which may be substituted,   R^ThreeIs hydrogen;   C₁~ C₈-Alkyl, C_Three~ C₆-Alkenyl, C_Three~ C₆-Alkynylma
Or C_Three~ C₈-Cycloalkyl, in which case these groups are each
Mono- or polysubstituted: hydroxy, mercapto, carboxy
, Halogen, nitro, cyano, C₁~ C_Four-Alkoxy, C_Three~ C₆-Arkeni
Roxy, C_Three~ C₆-Alkynyloxy, C₁~ C_Four-Alkylthio, C₁~
C_Four-Halogenalkoxy, C₁~ C_Four-Alkylcarbonyl, C₁~ C_Four-A
Lucoxycarbonyl, (C₁~ C_Four-Alkyl) NH carbonyl, (C₁~ C_Four -Alkyl)_Two-N carbonyl, C_Three~ C₈-Alkylcarbonylalkyl, a
Mino, NH (C₁~ C_Four-Alkyl), N (C₁~ C_Four-Alkyl)_Two, Feno
Xy or phenyl, heteroaryl, which is 5 or 6 membered, 1-3
Has one nitrogen atom and / or one sulfur or oxygen atom,
Wherein the aryl and heteroaryl groups may be substituted;
Is   Optionally substituted phenyl or naphthyl; or   5- or 6-membered heteroaromatic ring, which has 1 to 3 nitrogen atoms and / or
Has one sulfur atom or oxygen atom, and each may be substituted.
Yes;   R^FourAnd R⁵(May be the same or different):   Optionally substituted phenyl or naphthyl; or   Direct bond at ortho position, methylene group, ethylene group or ethenylene group, oxygen source
Child or sulfur atom, or SO_TwoVia a-, NH- or N-alkyl- group
Bound to each other by phenyl or naphthyl; or   C_Three~ C₇-Cycloalkyl;   X and Y (may be the same or different):   Nitrogen or methine; where Z = nitrogen in the case of X = Y = methine;   Z is nitrogen or CR¹⁰;   Q is nitrogen or CR¹¹However, in that case, when X = Y = Z = nitrogen, Q = C
R¹¹;   R¹⁰Is hydrogen, halogen, hydroxy, NH_Two, NH (C₁~ C_Four-Archi
Le), N (C₁~ C_Four-Alkyl)_Two, C₁~ C_Four-Alkyl, C_Two~ C_Four-A
Lucenil, C_Two~ C_Four-Alkynyl, C₁~ C_Four-Hydroxyalkyl, C₁~
C_Four-Halogenalkyl, C₁~ C_Four-Alkoxy, C₁~ C_Four− Halogen
Coxy or C₁~ C_Four-Alkylthio, or CR¹⁰Is CR¹¹along with
Forming a 5- or 6-membered alkylene ring or alkenylene ring, wherein the ring is 1
Or two C₁~ C_Four-May be substituted by an alkyl group, and at that time
, One or more methylene groups each represent oxygen, sulfur, -NH or -N (
C₁~ C_Four-Alkyl); or   Optionally substituted phenyl;   R¹¹Is hydrogen, hydroxy, NH_Two, NH (C₁~ C_Four-Alkyl), N (
C₁~ C_Four-Alkyl)_Two, Halogen, C₁~ C_Four-Alkyl, C_Two~ C_Four-A
Lucenil, C_Two~ C_Four-Alkynyl, C_Three~ C₆-Alkenyloxy, C₁~ C _Four -Alkylcarbonyl, C₁~ C_Four-Alkoxycarbonyl, C₁~ C_Four-Hi
Droxyalkyl, C₁~ C_Four-Halogenalkyl, C₁~ C_Four-Alkoxy,
C₁~ C_Four-Halogenalkoxy, -NH-O-C₁~ C_Four-Alkyl, C₁~
C_Four-Alkylthio, C_Three~ C₈-Cycloalkyl or CR¹¹Is R¹⁰In
CR as listed¹⁰Forming a 5- or 6-membered ring with;   Phenyl or phenoxy, each optionally substituted; or   5- or 6-membered heteroaromatic ring, which has 1 to 3 nitrogen atoms and / or
Has one sulfur atom or oxygen atom, and each may be substituted.
I   A is a sulfur or oxygen] carboxylic acid derivative and a physiologically tolerable salt and
And pure enantiomers as well as pure diastereomers. 2. Use of the carboxylic acid derivative I according to claim 1 for treating a disease. 3. Use of compound I according to claim 1 as an endothelin receptor antagonist. 4. Use of the carboxylic acid derivative I according to claim 1 for the manufacture of a medicament for treating diseases in which elevated endothelin levels are manifested. 5. Use of the carboxylic acid derivative I according to claim 1 for the manufacture of a medicament for the treatment of diseases in which endothelin contributes to development and / or progression. 6. A carboxylic acid derivative I according to claim 1 for treating chronic heart failure, restenosis, hypertension, pulmonary hypertension, acute / chronic renal failure, cerebral ischemia, asthma, benign prostatic hyperplasia and prostate cancer. use. 7. A carboxylic acid derivative of formula I according to claim 1 mixed with a renin-angiotensin system inhibitor, such as a renin inhibitor, angiotensin-II-antagonist, angiotensin-converting enzyme (ACE) inhibitor. ACE
/ A combination with one or more agents selected from neutral endopeptidase (NEP) inhibitors, β-blockers, diuretics, calcium antagonists and VEGF blockers. 8. A pharmaceutical preparation for oral, parenteral and intraperitoneal administration, which contains at least one carboxylic acid derivative I according to claim 1 in addition to the usual pharmaceutical additives per dose.