WO1991019693A1 - Esters and cyclic diesters of 4-hydroxy-1,3-benzenedimethanol and compositions and methods employing such compounds - Google Patents

Abstract

Novel compounds selected from the group consisting of: (A) compounds of formula I(1), wherein: one of R?1 and R2¿ represents the group (a) and the other represents hydrogen or R?7CO-; R5¿ represents C¿1? to C6-alkyl or the group -(CH2)n-Z-(CH2)m-Ar; Z represents O, S or -CH2-; n represents an integer of 1 to 8; m represents zero or an integer of 1 to 8; R?7¿ is C1 to C10 alkyl, C3 to C8 cycloalkyl, aryl, heteroaryl, -N(R?9R10), or R11O-; R3, R4, R9, and R10¿ are each independently selected from hydrogen, C1 to C6 alkyl and Ar?1; R6 and R11¿ are each independently C1-C8 alkyl; Ar and Ar1 are each independently selected from the group consisting of phenyl or substituted phenyl, (B) compounds of formula I(2), wherein: R5a represents C¿1? to C6-alkyl or the group -(CH2)n-Z-(CH2)m-Ar?2; Ar2¿ is selected from the group consisting of phenyl, substituted phenyl, or phenyl optionally substituted by two adjacent groups which together form an additional benzenoid ring; ring Q represents one of the rings Q¿1?, Q2, Q3 or Q4, and pharmaceutically acceptable acid addition salts thereof are described. These compounds possess favorable properties for the treatment of asthma and all types of chronic, obstructionary bronchopulmonary diseases.

Description

ESTERS AND CYCLIC DIESTERS OF 4-HYDROXY-1.3- BENZENEDIMETHANOL AND COMPOSITIONS AND

METHODS EMPLOYING SUCH COMPOUNDS

BACKGROUND OF THE INVENTION

This invention relates to certain esters, ethers and cyclic diesters of known β2-agonists, which esters, ethers and cyclic diesters possess favorable properties for the treatment of asthma and all types of chronic obstructionary pulmonary diseases (COPD).

β₂-agonists are well known in the art, e.g. albuterol which is described in U.S. Patent No. 3,644,353. Certain esters of albuterol or compounds closely related to albuterol have also been described, e.g. in U.S. Reissue Patent No. 30 241 , British Patent No. 1,298,771 , U.S. Patent No. 3,904,671. However, none of these publications describe or suggest the ester, ethers or cyclic diesters of this invention.

SUMMARY OF THE INVENTION

This invention provides compounds selected from the group consisting of:

(A) Compounds of the Formula 1(1):

wherein: one of R¹ and R² represents the group

and the other represents hydrogen or R⁷CO-;

R5 represents Ci to Cβ-alkyl or the group -(CH2)π-Z-(CH2)m-Ar; Z represents O, S or-CH2~; n represents an integer of 1 to 8; m represents zero or an integer of 1 to 8; R⁷ is C1 to C10 alkyl, C3 to C8 cy oalkyl, aryl, heteroaryl, -N(R9RiO), or RiⁱO-;

R³, R⁴, R⁹, and R¹⁰ are each independently selected from hydrogen, C1 to C6 alkyl and Ar¹ ;

R⁶ and R¹¹ are each independently C1-C8 alkyl; Ar and Ar¹ are each independently selected from the group consisting of phenyl or phenyl substituted by one or two substituents selected from the group consisting of, R¹², R¹³0-, R¹⁴S(0)_x-, R¹⁵CO-, (R¹6R¹⁷)NCO-, F, Cl, Br, I, N0₂, CF₃, CN, or phenyl, wherein x is 0, 1 , or 2;

R¹², R¹³, R¹⁴, R¹⁵, R¹⁶, and R¹⁷ each independently represents an alkyl group having 1 to 6 carbon atoms;

(B) Compounds of the Formula 1(2):

wherein:

R5a represents Ci to Cβ-alkyl or the group -(CH₂)n-Z-(CH₂)m-Ar²;

Z represents O, S or-CH2-; n represents an integer of 1 to 8;

Ar² is selected from the group consisting of phenyl, phenyl substituted by one or two substituents selected from the group consisting of: hydrogen, R1 , R1³0-, R¹⁴S(0)_x-, R15CO-, (R16R1⁷)NC0-, F, Cl, Br, I, N0₂, CF3, CN, or phenyl, wherein x is 0, 1 , or 2; or phenyl optionally substituted by two adjacent groups which together form an additional benzenoid ring; m is an integer of from 1 to 8; ring Q represents one of the rings Q1 , Q₂, Q3 or Q4 below:

X is N or C-R¹⁸;

Y is N or C-R²¹; W represents O or S; each of R¹⁸, R¹⁹, R²⁰ and R²¹ is independently selected from hydrogen, C-ι-C₆ alkyl, Cι-C₆ alkoxy, Cl, F, Br, I, N0₂, CF₃, CN, R ²-S(0)y-, R²³-CO-, (R R²5)NCO- or phenyl, wherein y is 0, 1 or 2 and each R²², R²³, R²⁴ and R²⁵ is independently Ci-Cβ alkyl, or, in the ring Qi, two adjacent groups, (i.e., R¹³R¹⁹, R¹⁹R²° or R²°R²¹) which may form together an additional fused benzenoid ring; and (C) pharmaceutically acceptable acid addition salts of compounds of Formulae 1(1 ) and 1(2).

The compounds of Formulae 1(1 ) and 1(2) are preferably pharmaceutically acceptable acid addition salts.

In the compounds of Formulae 1(1) and 1(2), R⁵ and R^5a preferably represent tertiary-C.tHg, 1S0-C3H7 or

-(CH₂)_n-0-(CH₂)_m-phenyl wherein n and m independently are integers of 2 to 6.

In the compounds of the invention represented by the Formula 1(1), R¹ preferably represents

and R² preferably represents

R⁷ — CO—

wherein R³, R⁴, R⁶ and R⁷ are as defined above. Alternatively, R¹ preferably represents

R⁷ — CO—

and R² preferably represents

wherein R³, R⁴, R⁶ and R⁷ are as defined above. For compounds of Formula 1(1 ), R³ and R⁴ both preferably represent H. R⁶ preferably represents C3 to C4 alkyl. R⁷ preferably represents C . to CQ alkyl, phenyl, substituted phenyl, or unsubstituted heteroaryi, more preferably, Ci to Cβ alkyl, phenyl or substituted phenyl.

The compounds of Formula 1(1 ) preferably have the structural configuration

wherein R¹, R² and R⁵ are as described above.

Representative compounds of Formula 1(1 ) have the structural formula

The most preferred compound of Formula 1(1) is:

In the compounds represented by the Formula 1(2), Q preferably represents the ring Q., and Qi preferably is

wherein X is N or C-R¹⁸, and Y is N or C-R²¹ with the proviso that X and Y are not both N; each of R¹⁸, R¹⁹, R²⁰ and R²¹ is independently, selected from hydrogen, Ci to Cβ alkyl, Ci to CQ alkoxy, Cl, F, Br, I, N0₂, CF₃, CN, R -S(0)y-, R²³-CO-, R R25N-CO- or phenyl, wherein y is 0, 1 or 2 and each R²², R²³, R²⁴ and R 5 is independently C-j to C₆ alkyl, or, in the ring Qi, two adjacent groups, i.e. R¹⁸R¹⁹, R¹⁹R²⁰ or R²⁰R²¹, may form together an additional fused benzenoid ring.

Even more preferred compounds of Formula 1(2) are those compounds wherein Q is as described just above and one or two of R¹⁸, R¹⁹, R²⁰, and R²¹ are independently selected from F, Cl, CF₃, CH₃ and C2H5 and the remainder of these substituents are H.

Also preferred are compounds of Formula 1(2) wherein Q represents the ring Q₂ or ring Q3 or Q4.

Another preferred embodiment of compounds of Formula 1(2) relates to compounds wherein Q represents the ring

Qi wherein one of R¹⁹ and R²⁰ is hydrogen and the other is H, F, Cl, CF3, CH₃ or C₂H₅.

Still another preferred embodiment of compounds of Formula 1(2) involves compounds wherein Q represents the ring

Qi and wherein either Y is C-R²¹ and X is N; or X is C-R¹⁸ and Y is N, and R1S and R²¹ are H, F, Cl, CF_3> CH₃ or C₂H₅.

Especially preferred compounds of Formula 1(2) have the configuration at the carbon atom indicated by ^*

wherein R^5a is as above described.

Representative compounds of Formula 1(2) include:

NH(CH₂)6-O-(CH 2)₄-_P enyl

NHC(CH₃)₃

The most preferred compounds of Formula 1(2) are:

The compounds of this invention provide bronchodilating activity and accordingly are useful in the treatment of chronic obstructionary pulmonary diseases such as asthma. The invention also relates to pharmaceutical compositions comprising a compound of Formula I above in salt form in combination with a pharmaceutically acceptable carrier and methods of treating asthma, asthmatic bronchitis and other forms of obstructive pulmonary disease by administering an effective amount of a compound Formula I above for such purpose.

DETAILED DESCRIPTION OF THE INVENTION

The following terms used in the specification and claims have the meanings indicated below, unless otherwise indicated.

Alkyl (including the alkyl portions of alkoxy, alkylthio, etc.) - represents a straight or branched, saturated hydrocarbon chain having the number of carbons designated. For example, C1 to C6 alkyl refers to an alkyl, as described just above, having 1 to 6 carbon atoms. Aryl represents phenyl, 1-naphthyl, 2-naphthyl, phenanthrenyl, anthracenyl and indanyl, wherein the aryl group may be substituted by 1 to 3 substituents selected from the same group of substituents which may be attached to phenyl as hereinabove described and the aryl group may be attached via any ring carbon atom not occupied by another substituent.

Heteroaryi represents a cyclic group having at least one O, S and/or N interrupting a carbocyclic ring structure and having a sufficient number of delocalized pi electrons to provide aromatic character, with the aromatic heterocyclic group having from 2 to 14, preferably from 2 to 6 carbon atoms, e.g., 2-, 3- or 4-pyridyl, 2- or 3-furyl, 2- or 3-thienyl, 2-, 4- or 5-thiazolyl, 2-, 4- or 5-imidazolyl, 2-, 4- or 5- pyrimidinyl, 2-pyrazinyl, 3- or 4-pyridazinyl, 3-, 5- or 6-[1 ,2,4-triazinyl], 3- or 5-[1 ,2,4-thiadizolyl], 2-, 3-, 4-, 5-, 6- or 7-benzofuranyl, 2-, 3-, 4-, 5-, 6- or 7-indolyl, 3-, 4- or 5-pyrazolyl, 2-, 4- or 5-oxazolyl, etc., wherein the heteroaryi group may be substituted by 1 to 3 substituents selected from the same group of substituents which may be attached to phenyl as hereinabove described and the heteroaryi group may be attached via any ring carbon atom not occupied by another substituent. Preferred heteroaryi groups are 2-, 3- or 4-pyridyl, 2- or 3-furyl, 2- or 3-thienyl, 2-, 4- or 5-imidazolyl or 7-indolyl.

Certain compounds of this invention may exist in isomeric forms. The invention contemplates all such isomers both in pure form and in admixture, including racemic mixtures.

Certain compounds of the invention can exist in unsolvated as well as solvated forms, including hydrated forms, e.g., hemihydrate. In general, the solvated forms, with pharmaceutically acceptable solvents such as water, ethanol and the like are equivalent to the unsolvated forms for purposes of the invention.

The compounds of the invention form pharmaceutically acceptable salts with organic and inorganic acids. Examples of suitable acids for such salt formation are hydrochloric, sulfuric, phosphoric, acetic, citric, oxalic, malonic, salicylic, malic, fumaric, succinic, ascorbic, maleic, methanesulfonic and other mineral and carboxylic acids well known to those skilled in the art. The salts are prepared by contacting the free base form with a sufficient amount of the desired acid to produce a salt in the conventional manner. Alternatively, the salts are prepared by contacting the free base form of a suitable precursor such as a compound of Formula VI(a) or (b) as described below with a sufficient amount of the desired acid to produce a salt in the conventional manner, and carrying these intermediates through to the final products according to the procedures described below. The free base forms differ from their respective salt forms somewhat in certain physical properties, such as solubility in polar solvents, but the salts are otherwise equivalent to their respective free base forms for purposes of this invention.

The compounds of this invention may be prepared according to methods well known in the art. In the reaction schemes below, R¹, R², R³, R⁴, R⁵, R⁸, and R⁷ are as described above unless otherwise noted.

The compounds of Formula 1(1 ) may be prepared in accordance with Reaction 1 :

III

IVa

Via

In the above Formulae, L¹ is a leaving group, e.g., halogen such as bromine, chlorine, or iodine, with iodine being preferred because L¹ is iodine in the immediately preceding step of the chemical synthesis; and L² represents a protecting group such as benzyl, alkyl- or alkoxy-substituted benzyl, or benzhydryl.

Step A is preferably carried out in a neutral solvent, e.g., dimethylformamide (DMF), methyl ethyl ketone, or more preferably, acetone, in the presence of a base, e.g., sodium carbonate, cesium carbonate, or more preferably, K₂C03, by rapidly adding a solution of compound III to compound II at room temperature under an inert atmosphere such as argon or nitrogen. The reaction is conducted for a period of about 1 to about 100 hours, and the resulting product of Formula IVa may be isolated by conventional means.

In the above reaction, the compound of Formula III may be prepared in situ. For example, the corresponding compound of Formula III, that is, a compound of Formula

wherein R³, R⁴, and R⁶ are as described above, and X' is chloro may be reacted with a salt such as sodium iodide, or more preferably, potassium iodide, in the presence of a solvent such as an aliphatic ketone, preferably acetone, to obtain a compound of Formula HI in which L¹ = I, which is reacted in situ with a compound of Formula π as described above. This in situ reaction is carried out at about room temperature in an inert atmosphere such as argon or nitrogen.

If a compound of Formula la, wherein R² is hydrogen is desired, then compound IVa obtained by reaction step A or preferably an acid addition salt thereof may be subjected to removal of the protecting group L². For example, if L² is benzyl it may be removed by hydrogenolysis. The hydrogenolysis may be carried out in a polar organic solvent such as acetic acid or an alcohol, like ethanol, butanol, or more preferably a mixture of methylene chloride and isopropanol. The reaction is carried out in the presence of a hydrogenation catalyst such as Pt0₂, Pt on carbon, or Pd on carbon, more preferably 10% Pd- C. The hydrogenation is done in about 1 to about 3 atmospheres of H2, preferably about 1 atmosphere of H2 for a period of about 0.25 to about 30 hr., preferably about 0.25-3 hours. Isolation of the thus obtained compound of Formula 1(1) can be by conventional means such as filtration followed by evaporation of the solvent, and purification of the residue by column chromatography.

In step B of the above process a compound of Formula IVa is reacted with an acid chloride (R⁷COCI) or acid anhydride (R⁷CO)2θ to yield a compound wherein R² is R⁷-CO. The reaction is preferably carried out in a neutral solvent, e.g., CHCI3, or preferably CH2CI₂, in the presence of a base such as pyridine, diisopropylethyl- amine, or more preferably triethylamine at temperatures between -78° and 0°C under an inert atmosphere such as argon or nitrogen. Preparation of the acid addition salt and removal of the protecting group L², e.g. as described above, result in an acid addition salt of a compound of Formula 1(1) (Step C). if in step A above, the reaction is carried out by dropwise addition of compound π in a neutral solvent, or more preferably acetone, to a solution of III in acetone, a compound of Formula IVb below is obtained. By following the further reactions outlined above, compounds of Formula 1(1 ) wherein R¹ is hydrogen or R -CO, i.e. compounds of Formula lb are obtained through the intermediate VIb set forth just below.

The following reaction steps also lead to compounds of Formula 1(1) wherein R¹ is R⁷-CO: Reaction 2:

lb

In step D the triol II is reacted with an acid chloride or acid anhydride as described under step B in Reaction 1 above resulting in a compound of Formula VII which may be isolated and purified by flash chromatography. Reaction of a compound of Formula VII with a compound of Formula IH (see step A, Reaction 1 ) in a neutral solvent, e.g., acetone, in the presence of a base, e.g., K₂Cθ3, results in a compound of Formula VIb which is then transformed into an acid addition salt by treatment with a slight excess of acid, e.g. HCI. The salt is dissolved in isopropyl alcohol (using CH2CI2 as a cosoivent if necessary) and treated with hydrogen over 10% Pd-C. The so obtained compound of Formula lb is purified by flash chromatography, short path column chromatography or reversed phase HPLC (high performance liquid chromatography).

In a method (A) for preparing compounds of Formula 1(2), an alcohol of the Formula II

wherein R⁵ and L² are as described above, is reacted with an acid chloride of the Formula XIV

wherein Q is as described above for Formula 1(2), to yield a compound of Formula XV

wherein Q, L² and R⁵ are as described above, followed by removal of the protecting group L² as described below. The reaction is conducted in a suitable solvent such as CH₂CI₂ at a temperature in the range of about 0°C to about -78°C in the presence of a base such as triethylamine or diisopropylethylamine. The addition of a catalytic quantity of dimethylaminopyridine (DMAP) may aid the reaction, depending on the structure of the diacid chloride. The resulting compound of Formula XV can be used without purification in the next step. The second reaction is carried out in a mixture of an alcohol, preferably isopropanol and a halogenated solvent, preferably CH CI . An equivalent amount, or a slight excess of acid, preferably CF₃CO2H, is added to the solution of substrate and to the mixture is added a suitable catalyst, preferably 2-10% Pd-C (palladium on charcoal). The stirred suspension is hydrogenated in an atmosphere of hydrogen, following the conversion of starting material from time to time by thin layer chromatography.

Another method (B) for preparing compounds of Formula 1(2) comprises reacting an alcohol of Formula II with an acid anhydride of the Formula XVI

XVI

wherein Q is as described above, to yield a monoester of the Formula XVII

wherein Q, L² and R⁵ are as described above, followed by a second esterification step yielding a compound of Formula XV, which compound is further treated as above. The first esterification step is conducted in a suitable solvent such as pyridine or more preferably CH₂CI₂ at a temperature from about -78°C to about 0°C. The second esterification step is conducted in a suitable solvent such as CH₂CI₂. It is further conducted in the presence of an acid anhydride, such as trifluoroacetic anhydride, and an organic base, such as triethylamine at a temperature of from about -10°C to about 25°C. This step may also be conducted in the presence of 1,3-dicyclohexylcarbodiimide. The L² group is removed as described below.

In still another method (C) for preparing a compound of Formula 1(2), a compound of Formula XVIII

wherein Q is as described above, may also be reacted with a compound of Formula X

wherein L² and R⁵ are as described above, to yield a compound of Formula XV followed by removal of the protecting group L² as described below. The reaction is conducted in a solvent such as an alcohol or dimethylformamide, toluene or more preferably in a mixture of isopropanol and CH2CI2, at a suitable temperature such as room temperature in the presence of a hydrogenation catalyst such as 10% Pd-C under about 1 atmosphere H₂. Isolation of the resulting compound of Formula 1(2) can be by conventional means such as column chromatography. In yet another method (D) of preparing a compound of Formula 1(2), the L² group of a compound of the Formula XIX

wherein Q, L² and R⁵ are as described above and T represents C=0, may be removed and the carbonyl group, represented by T, reduced to -CH(OH)-, to yield a compound of Formula 1(2).

The starting compounds used in the reactions described above are either known compounds or may be obtained by reaction steps well known in the art for preparing similar compounds, e.g., by following the reactions indicated below:

I

In reaction F, reduction of the carbonyl group in compound Vπi with NaBH4 leads to a starting compound of Formula π. The reduction is carried out in a solvent such as an alcohol, or more preferably, isopropanol at a temperature of from about -10°C to about 20°C. A compound of Formula II may also be obtained by reaction of the amine of Formula X with the epoxide of Formula IX in a neutral solvent such as tetrahydrofuran (THF), DMF, toluene, or more preferably, CH₂CI2 at a temperature of from about -10°C to about 35°C (e.g., about -10°C to about 30°C). The resulting compound XI is then hydrolyzed to eliminate the protecting groups L³ and L⁴. The hydrolysis is by conventional means. For example, a compound of Formula XI may be reacted with an acid such as aqueous HCI, or more preferably aqueous H2SO4. The temperature is from about 10°C to about 40°C.

Alternatively, the hydrolysis may be conducted with a base such as an inorganic hydroxide, preferably NaOH or KOH. The temperature is from about 10°C to about 50°C. Compounds of Formula Viπ may be prepared by reacting a compound XII, wherein Hal is halogen and preferably is Cl or Br, with an amine of Formula X followed by removal of the protecting groups L³ and L⁴ by hydrolyses. The reaction with the amine is conducted in a neutral solvent such as THF, DMF, toluene, or preferably CH2CI2 at a temperature from about -10°C to about 30°C (e.g., about 0°C to about 30°C). These hydrolyses are conducted similarly to hydrolyses described above. The reaction of method D above, i.e., removal of the protective group L² and reduction of the carbonyl function represented by T can be carried out in one or two steps. The one step reaction, which is preferred, comprises a single step hydrogenolysis/carbonyl reduction using metal catalysts, e.g., 5-10% Pd-C under an atmosphere of hydrogen in a solvent, e.g., a mixture of isopropanol and methyiene chloride. In the two step process, the carbonyl group is reduced, and the protecting groups are removed by conventional methods to yield a compound of the Formula EL R⁵ is as defined for Formula II and L², L³ and L⁴ represent standard protecting groups . For example, L² may be benzyl or substituted benzyl, whereas L³ and L⁴ may be ester groups, such as lower acyl (e.g., acetyl or benzyl), or L³ and L⁴ may be joined together to form a ring in which a -CH2-, -CHCH3-, or -CH(phenyl)- bridges the two oxygen atoms.

Compounds of Formula IX are well known in the art! e.g. from British Patent No. 2 140 800 A and German Patent No. 2 310 141. Compounds of Formulae vm, X, XI, XII, and XIII, and the acid chlorides and anhydrides of Formulae XIV and XVI are also known or can be prepared in accordance with known methods. The starting compounds of Formula XVm may be obtained by the following reaction steps:

VIII

wherein Q is as described above. DBN is 1 ,5-diazabicyclo[4.3.0]non-5- ene and DBU is 1 ,8-diazabicyclo[5.4.0]undec-7-ene.

Compounds of Formula XIX may be obtained by careful reaction of compounds of Formula XXII with an amine of Formula X at low temperature (0°C to -78°C). The reaction is conducted in a solvent such as dimethylformamide, toluene, or more preferably CH2CI2. The resulting compound of Formula XIX can be isolated by conventional means such as column chromatography.

Compounds of Formula XIX may also be obtained by esterification reactions as described in methods A and B above, by reacting the acid chlorides XIV or anhydrides XVI, with a ketone of Formula XXIII

wherein T, L² and R⁵ are as described above. The compounds of Formulae XX and XXiπ are known or can be prepared by methods known in the art. The compounds of the invention provide bronchodilating activity with enhanced duration of activity compared to known unprotected diols. Such enhanced duration of activity varies with the R², R³ and Q groups employed. 5 The bronchodilator activity provided by the compounds of the invention may be demonstrated by the following test protocol.

INHIBITION OF HISTAMINE INDUCED BRONCHOSPASM

ι o Procedure:

Male Charles River Hartley strain guinea pigs are fasted overnight but allowed H2O ad lib. At -20 minutes, the animals are anesthetized with I.P. dialurethane. About 4 minutes later, the animals are shaved in the neck area and placed on their backs on a platform,

15 inclined head up at 45° from horizontal. An incision is made through the skin and muscle/fascia teased apart to expose the trachea. Forceps are placed behind the trachea to hold it rigid while a 25 g 5/8" needle attached to a 1cc syringe is inserted between cartilage rings pointing caudal I y into the lumen of the trachea and 0.2 ml_ of control vehicle

20 (saline) or test compound (3μg in 0.2 ml_) is injected slowly intratracheally at -15 minutes. Then the needle and forceps are removed . The animal is then transferred to a platform inclined at about 30° from horizontal (still on its back) and surgically prepared by installing an intratracheal tube. The animal is respi rated during surgery.

25 The animals are then transferred to a respirator and monitored for insufflation pressure using a side-arm pressure transducer. Pump volume is 4.0 mL and the rate is 55 strokes/min. The animals are challenged at 0 minutes with an I.V. 10 μg/kg histamine (HA) bolus. A second I.V. HA challenge is given at +30 minutes (i.e. 45 minutes post

30 I . drug treatment).

Separate studies are conducted to determine whether bronchodilator activity lasted 3 hours. In these studies, the animals are first anesthetized with the short acting ingredient Brevital. Under anesthesia, the trachea is exposed and the compound is given, as described above. The animal recovers from the anesthesia within 30 minutes and is allowed free movement for the next 2 hours. At that time, the animals are anesthetized with dialurethane and surgically prepared for the measure of insufflation pressure and I. V. challenge with histamine (3 hours after drug treatment) as described above.

Results obtained in the above procedures are shown in Tables 1 and 2, and expressed as a percent inhibition of the bronchospasm (increased insufflation pressure) due to histamine.

In Table 1 , the first dose, 3 μg (second column from left in Table 1 ) was used to test for onset of activity at 15 minutes, whereas the second dose, 15 to 25 μg, (fourth column from the left in Table 1) was used to test for duration of activity at 3 hours. In Table 1 , "inhib" stands for "inhibition".

TABLE 1 ACTIVITY IN GUINEA PIG BRONCHOSPASM ASSAY

STRUCTURE Dose % Dose % (μg) inhib (μg) inhib

TABLE 1 Continued

STRUCTURE Dose % Dose %

(μg) inhib (μg) inhib

TABLE 1 Continued

STRUCTURE Dose % Dose' %

(μg) inhib (μg) inhib

TABLE 1 Continued

STRUCTURE Dose % Dose %

(μg) inhib (μg) inhib

TABLE 1 Continued

STRUCTURE Dose % Dose %

(μg) inhib (μg) inhib

15 63

TABLE 1 Continued

STRUCTURE Dose % Dose % (μg) inhib

STRUCTURE Dose % Dose % (μg) inhib (μg) inhib

OH H

(CH₃)₃C

c^£° 3 0

TABLE 2

rin Q Activit^y at 15 min. Activity at 45 min. Activitv at 3 hrs.

48 11

The active compounds can be administered orally, but are preferably delivered via aerosol, e.g., via oral or nasal inhalation.* The compounds can be administered in conventional oral dosage forms such as capsules or tablets prepared with conventional pharmaceutically acceptable excipients and additives, using conventional techniques. Inhalation administration can be in the form of a nasal or oral spray. Insufflation is also contemplated.

For preparing pharmaceutical compositions from the compounds described by this invention, inert, pharmaceutically acceptable carriers can be either solid or liquid. Solid form preparations include powders, tablets or capsules. The powders and tablets may comprise from about 5 to about 70 percent active ingredient. Suitable solid carriers are known in the art, e.g., magnesium carbonate, magnesium stearate, talc, sugar, lactose.

Aerosol preparations suitable for inhalation may include solutions and solids in powder form, which may be in combination with a pharmaceutically acceptable carrier, such as an inert compressed gas. Normally, the formulation will be delivered from a dispensing or inhaling device, which would provide the preferred metered dose of the compound of the invention.

The oral dosage range is about 2 to about 20 mg daily per adult patient. This amount may be given in divided doses. For example two 10 mg capsules may be given to an adult patient for one day.

Preferably, the pharmaceutical preparation is in aerosol form. In such form, the preparation is delivered as unit doses containing appropriate quantities of the active component, e.g., an effective amount to achieve the desired purpose. When used in this way for the treatment of bronchoconstriction, the compounds of the invention can be administered in an amount ranging from about 50 μg to about 1000 μg per puff, preferably about 100 μg to about 500 μg per puff. A typical recommended dosage regimen is administration of from about 100 to about 2000 μg/day, preferably from about 200 to about 1000 μg/day, in two to four doses to achieve relief of the symptoms of bronchoconstriction.

Determination of the proper dosage of a compound of the invention for a particular situation is within the skill of the art. Generally, treatment is initiated with smaller dosages that are less than the optimum dose of the compound, Thereafter, the dosage is increased by small increments until the optimum effect under the circumstances is reached. For convenience, the total daily dosage may be divided and administered in portions during the day if desired.

The amount and frequency of administration of the compounds of Formulae 1(1) and 1(2), and the pharmaceutically acceptable salts thereof, will be regulated according to the judgment of the attending clinician considering such factors as age, condition and size of the patient as well as severity of the symptoms being treated.

The compounds of this invention are believed to be non-toxic when administered in the dosages described above.

The invention disclosed herein is exemplified by the following preparative examples, which should not be construed to limit the scope of the disclosure. Alternative mechanistic pathways and analogous structures within the scope of the invention will be apparent to those skilled in the art.

EXAMPLE 1

The starting material, prepared in essentially the same way as described in Preparative Example 3 below, (0.616 g), was dissolved in CH2CI2 (5 mL) and isopropanol (IPA) (5 mL) in a hydrogenation flask containing 10% Pd-C (61.6 mg) flooded with N₂ gas. Methanesulfonic acid (78.3 μL) was added dropwise to the stirred solution. The suspension was stirred in hydrogen atmosphere. The reaction was followed by (Thin Layer Chromatography) TLC until complete (about 2 hrs.).

The catalyst was removed by filtration and the solvents were evaporated under vacuum to yield an amber oil which was purified by column chromatography on silica gel eluting with CH2CI2/10% methanol. The product, located by TLC, was obtained by evaporation of the relevant fractions and was dried under high vacuum overnight to yield 0.387 g of a hygroscopic white solid, which was shown to be a hydrated HCI salt of the desired material.

Analysis: For C27H37Nθ6^»HCI^« O.75H2O

Found: C; 61.87; H, 6.55; N, 2.73

Theory: C, 62.18; H, 7.63; N, 2.66

FAB-MS: m/e 472 (M+1)

EXAMPLE 2

The product from Preparative Example 3, (2.39 g) was dissolved/suspended in IPA (238 mL). A slight excess of 20% HCI in methanol (0.88 mL) was added, the mixture was stirred for 10 min. and it was then evaporated to a white solid. This solid was redissolved in a mixture of methanol (23.8 mL) and ethanol (214.2 mL). To this solution was added 10% Pd-C (1.195 g) while the flask was flushed with N2. The mixture was stirred and hydogenolyzed under 1 atmosphere of H₂. The progress of the reaction was followed at about 15 minute intervals by reverse-phase high performance liquid chromatography (RP-HPLC). The reaction was terminated when dechlorination of the aromatic. halogen began to be seen (around 8% conversion to dechlorinated product; no starting material left).

The catalyst was filtered off, and the reaction mixture was evaporated to dryness under vacuum. The crude product was dissolved in methanol:water (50:50; minimum volume) and purified by preparative RP-HPLC using a C_.-coated 300A pore-size column with methanol (50%):water (50%), adjusted to pH 2.8-3.0 with HCI. The desired fractions were located by both TLC and RP-HPLC using a Whatman Partisil 5, ODS-3 (octadecyl silane) analytical column, eluting with methanol (80 parts): water (20 parts): 85% H3PO4 (1 part); sodium dodecyl sulfate (0.0025 M). Detection was by UV absoφtion at 230 nm. The combined fractions containing product were evaporated under reduced pressure, at or below room temperature, to remove methanol, then the product was extracted with CH2CI2 (3 X 1 L). The resulting solution was dried, filtered, and evaporated to yield the product as a white foam.

EXA PIE 3

The starting material (0.849 g) prepared as described in

Preparative Example 11 , was dissolved in IPA, to which was added 10% Pd-C (85 mg) and acetic acid (0.11 mL). The mixture was stirred in a hydrogen atmosphere and the reaction was followed by TLC. When the reaction was complete (ca. 4 hr.) the catalyst was filtered off and solvents were removed under vacuum. The residue was dried under high vacuum, triturated with hexane, then dried under high vacuum for 2 1/2 days to yield the acetate salt of the desired product as a hygroscopic glassy solid, 0.35 g.

Analysis: For C24H39NOyCH₃Cθ2H Found: C, 60.43; H, 8.24; N, 2.71

Theory: C, 60.80; H, 8.44; N, 2.72 FAB-MS; m/e 454 (M+1) E A PLE 4

The product from Prep. Example 4 (0.85 g) was dissolved in IPA (8 mL). To this solution was added 20% HCI in methanol (0.53 mL), and the solvent was removed by evaporation. The residue was dissolved in IPA (20 mL) and 10% Pd-C (86 mg) was added. The mixture was stirred and hydrogenolyzed at 1 atmos. until the reaction was completed (TLC).

The reaction mixture was filtered and evaporated to dryness under vacuum. The residue was purified by chromatography on a silica gel column eluting with CH2CI₂/12% methanol. Fractions containing the desired product were combined and evaporated to dryness over night. The yield of desired product as a hygroscopic white solid, was 0.06 g.

Analysis: For CιgH3iNθ5^»HCI^»H2θ Found: C, 55.40; H, 7.61 ; N, 3.26 Theory: C, 55.94; H, 8.40; N, 3.43 FAB-MS; m/e 354 (M+1) EXAMPLE 5

The product from Preparative Example 7 (0.65 g) was dissolved in IPA (10 mL), and 20% HCI in methanol (0.3 mL) was added. After stirring for 5 min. the solvent was removed by evaporation under vacuum. The residue was redissolved in CH2CI2 / IPA (13 mL of 1 :1 ), and 5% Pd-C (65 mg) was added. The mixture was stirred in an atmosphere of H2 for 2 h. The catalyst was removed by filtration through a Celite pad which was then rinsed with CH2CI2 / IPA (20 mL of 1 :1 ). The solvents were removed by evaporation under vacuum. The crude product was purified by column chromatography on silica gel elufing with 10% methanol / CH2CI2- Fractions containing the product, as shown by TLC, were combined and evaporated to yield the desired product, as the hydrochloride salt, as a white solid, 0.34 g, mp 181 - 184°C.

Analysis: For Ci9H ₁Nθ5^«HCI

Found: C, 58.52; H, 8.35; N, 3.48; Cl, 9.04 Theory: C, 58.67; H, 8.27; N, 3.59; Cl, 9.09

FAB-MS; m/e 354 (M+1) EXAMPLE 6

The product from Preparative Example 6 (0.7 g) was dissolved in IPA (14 mL) and 20% HCI/methanol (0.3 mL) was added. The mixture was stirred for 5 minutes. The solvents were removed under vacuum and the residue was dissolved in IPA (14 mL). To this solution was added 10% Pd-C (17 mg) and the mixture was hydrogenolyzθd at 1 atmosphere. The reaction was followed by TLC and was complete after about 2 hours. The mixture was filtered, and solvents were evaporated under vacuum. The residue was purified by flash chromatography on silica gel eluting with CH2Cl2:methanol (9:1 ). Fractions containing the desired product were combined and evaporated to a white solid, mp 40 - 41 °C (0.41 g).

Analysis: For C2δH4iNθ6^»HCI

Found: C, 61.16; H, 8.68; N, 2.75

Theory: C, 61.52; H, 8.67; N, 2.87

FAB-MS; m/e 452 (M+1) EXAMPLE

The product from Preparative Example 8 (0.933 g) was dissolved in CH2CI2 and to the solution was added 20% HCI in methanol (0.33 mL). The mixture was stirred for 5 min. then it was evaporated under vacuum to yield a white, fluffy solid.

This salt was dissolved in CH2CI2/IPA (10 mL of 1 :1) contained in a hydrogenation vessel. To the solution was added 10% Pd-C (98.5 mg) under an atmosphere of N2. The suspension was stirred in an atmosphere of H2 for 2 h. It was then filtered, and evaporated under vacuum to yield an amber oil. This crude product was purified by short-path column chromatography over silica gel, eluting with 5% methanol/CH2Cl2. After locating the product by TLC the relevant fractions were evaporated to yield the desired product, as its HCI salt, 0.35 g, mp 75 - 77°C.

Analysis: For C26H33 θ6Cl2^»HCI Found: C, 55.48; H, 5.99; N, 2.40 Theory: C, 55.42; H, 6.09; N, 2.49 By one of essentially the same procedures as described in Examples 6 and 7, using minor modifications well known to one skilled in the art, were prepared:

R7 =

IB

IE i:: / / ;; IIFF: (CH₃)2CHCH₂-; and IG: (CH₃)3CCH₂-

Compound (IA); mp 47 - 49°C Analysis: For C26H34N06CI^»HCI Found: C, 59.73; H, 6.76; N, 2.65 Theory: C, 59.09; H, 6.68; N, 2.65

FAB-MS; m/e 492/494, (M+1).

Compound (IB); mp 53 - 55°C Analysis: For C27H37Nθ6*HCI Found: C, 63.87; H, 7.51 ; N, 2.62; Cl, 6.81

Theory: C, 63.83; H, 7.53; N, 2.75; Cl, 6.97 FAB-MS; m/e 472, (M+1). Compound (IC); mp 54 - 57°C Analysis: For C24H33Nθ7^«HCI^«H2θ Found: C, 57.85; H, 7.09; N, 2.70; Cl, 6.66

Theory: C, 57.42; H, 7.22; N, 2.78; Cl, 7.06

5 FAB-MS; m/e 448 (M+1).

Compound (ID)

Analysis: For C24H33Nθ7^#HCI Found: C, 59.22; H, 7.02; N, 2.76; Cl, 6.76

10 Theory: C, 59.56; H, 7.08; N, 2.89; Cl, 7.33

FAB-MS; m/e 448 (M+1).

Compound (IE)

Analysis: For C24H33Nθ6*HCI 15 Found: C, 60.55; H, 8.70; N, 2.85; Cl, 7.10

Theory: C, 60.80; H, 8.50; N, 2.95; Cl, 7.47 FAB-MS; m e 438 (M+1).

Compound (IF); mp 168 - 171°C 20 Analysis: For C24H39NO6ΗCI

Found: C, 60.45; H, 8.30; N, 2.88

Theory: C, 60.80; H, 8.50; N, 2.95 FAB-MS; m/e 438 (M+1).

25 Compound (IG); C25H4.NO6

FAB-MS; m/e 452 (M+1).

EXAMPLE 8

The product from Preparative Example 9 (0.24 g) was dissolved in IPA (5 mL), and 20% HCI in methanol (0.1 mL) was added. After 5 min. of stirring at room temperature the solvents were evaporated off under vacuum. The residue was dissolved in IPA (7 mL), 10% Pd-C (24 mg) was added, and the mixture was hydrogenolyzed at room temperature and at 1 atmos. for about 2 h. The catalyst was removed by filtration through a Celite pad which was rinsed with CH2CI2 (50 mL). The combined organic solutions were evaporated under vacuum, and the resulting solid was triturated with ether to yield the desired product as a white, hygroscopic powder. Analysis: For C2.H33N07^»HCI

Found: C, 56.31 ; H, 7.76; N, 3.01 Theory: C, 56.31 ; H, 7.65; N, 3.13 FAB-MS; m/e 412 (M+1) EXAMPLE 9

The product from Preparative Example 3 (2.39 g) was dissolved / suspended in CH2CI2 (238 mL). A slight excess of 20% HCI in methanol (0.88 mL) was added. The mixture was stirred for 10 min. and was then evaporated to a white solid. This solid was redissolved in ethanol (239 mL). To this solution was added 10% Pd-C (1.95 g) while the flask was flushed with N2. The mixture was stirred and hydrogenolyzed under 1 atmos. of H2. The progress of the reaction was followed at ca. 15 min. intervals by RP-HPLC. The reaction was terminated when dechlori nation of the aromatic halogen began to be seen (ca. 2% conversion to dechlorinated product; trace of starting material left).

The catalyst was filtered off, and the reaction mixture was evaporated to dryness under vacuum. The crude product was dissolved in a mixture of CH2CI2 (90): IPA (10) and was purified on a short-path silica gel column made up in the same solvent. Fractions eluting from the column were monitored by RP-HPLC using an ODS-3 analytical column, eluting with methanol (80): water (20): H3PO4 (1): sodium dodecyl sulfate (0.0025 M) and detecting by UV absoφtion at 230 nm. Fractions containing product were combined and concentrated to a colorless syrup. This thick oil was dissolved in deionized water and lyophilized to a white powder.

Analysis: For C27H36Nθ6CI^»HCI

Found: C, 59.20; H, 7.20; N, 2.58 Theory: C, 59.77; H, 6.87; N, 2.58

FAB-MS; m/e 506/508 (M+1 for ³5ci and ³ CI respectively)

By an analogous procedure, using minor modifications well known to one skilled in the art, the compound shown below was prepared. For instance, the salt used in the debenzylation was derived from trifluoroacetic acid instead of HCI.

(CH2)6-O-(CH )4-phenyl

C39H53NO7CI; FAB-MS MW (of M+1 ion containing the

³⁵CI isotope) by peak matching = 682.3534 (calculated value, 682.3511).

Example 10

Preparation of 2-f2-r(1.1. -Dimethvlethvl .aminol-1 -hvdroxvethvπ-13H- dibenzofb.g1H.51-dioxonin-6.11-dione. acetic acid salt. 2.5 hvdrate. Method A

(i)

N-Benzyl-N-t-butyl-1-[2-hydroxy-5-hydroxymethyl]- phenethylamine (10.0 g) was dissolved in CH₂CI (anhydrous, 400 mL) and chilled to below about -70°C. Triethylamine (10.6 mL, 2.5 eq; distilled) was added. When the internal temperature fell to -78°C phthaloyi dichioride (5.06 mL, 1.1 eq) in CH₂CI₂ (40 mL) was added at a rate of about 5 mL/hr. The mixture was stirred under an atmosphere of nitrogen overnight, during which time the temperature reached room temperature. The solution was washed with 1% aqueous AgN0₃ and filtered to remove the precipitated AgCI. The CH₂CI₂ was dried (MgS0₄), filtered, and evaporated in vacuo to yield a yellowish solid. The product was purified by short-path column chromatography on 210 g of >230 mesh silica gel in 10% ethyl acetate/CH₂CI₂. The product was located by TLC and the relevant fractions were evaporated to a yellowish solid which was triturated with 40% ethyl acetate/hexane to afford a white solid. This material was used in the next step without further purification.

(ϋ)

The product from the previous step (0.2 g) was dissolved in a 1 :1 mixture of CH CI₂ and isopropanol (10 mL). To the stirred solution was added acetic acid (25 μL) and 10% Pd-C (0.02 g). The mixture was hydrogenolyzed at atmospheric pressure for about 20 hr. after which time the catalyst was filtered off and the solvent removed to yield an off-white solid.

The crude product was combined with the product from a second, similar run and was purified by short-path column chromatography over 15g of silica gel (finer than 230 mesh) made up in 5% MeOH in CH₂Cl2. Two fractions containing the bulk of the product were combined, acetic acid (1.2 equivalents) was added to convert the material completely into the acetate salt, and this material was chromatographed again in CH₂Cl2 in a methanol gradient starting at 1% and increasing to 8% methanol to yield the product, mp. 86-88°C.

Found, C, 57.86; N, 2.74.

Calcd. for C23H27N0₇ ^»2²/₃ H₂0, C, 57.85; N, 2.93.

EXAMPLE 11

(i)

The ketone-diol starting material, as its HCI salt, (10 g) was suspended in dry CH₂CI₂ (400 mL) under an atmosphere of dry N₂. To the suspension was added NEt₃ (5.745 mL; 1.5 equivs. relative to the HCI salt) resulting in the formation of an amber solution. In a separate reaction flask were placed o-phthaloyl dichloride (4.586 mL; 1.1 equivs. relative to the HCI salt), NEt₃ (7.66 mL; 2.0 equivs. relative to the HCI salt) and 4-(N,N-dimethylamino)-pyridine (DMAP; 1 g) all dissolved in CH₂CI₂ (300 mL) and cooled to around -70°C. The first solution was added dropwise to the second solution at such a rate that the internal temperature never rose above -69°C. After about 1.25 h, TLC showed that no starting material remained. The reaction mixture was stirred under nitrogen at -70°C overnight.

MeOH (4.5 mL) was added to the reaction mixture which was then stirred for 0.5 h. Next, AcOH (glacial) was added to neutralize the mixture. The product was washed with H₂0, satd. NaCI soln., and dried over MgS0 . After filtration the solvent was evaporated in a vacuum to yield ca. 12 g of yellowish crude product. The product was purified by short-path column chromatography on silica gel using 5% Et0Ac/CH₂Cl2 to yield 6.58 g of material which was used in the next step without further purification.

(ϋ)

The product from the previous step (6.58 g) was dissolved in CH₂CI₂/ isopropanol (132 mL; 1 :1 mixture). This solution was added to a hydrogenation flask containing 10% Pd-C (1.316 g) into which was being passed a stream of N₂. CF3CO2H (TFA; 1.219 mL; 1.1 equivs. based on the substrate) was added with stirring. The reaction suspension was stirred under 1 atmosphere of H₂ for about 7 hours. The catalyst was removed by filtration and the solvents were removed by evaporation under vacuum to yield an oil which was purified by short-path column chromatography on silica gel eluting with 10% MeOH/CH₂CI₂. The product from this column was further purified by separation on a second similar column using 5%MeOH/CH₂CI₂ as the eluant. The product was a colorless gum or glass.

Found, C, 55.82; H, 5.10; N, 2.48. Calcd. for C2₃H24Nθ7F₃ ^«2/3 H₂0, C, 55.76; H, 5.15; N, 2.83 EXAMPLE 12

Preparation of Pvridine-2.3-dicarboxvlic acid dichloride.

A mixture of pyridine-2,3-dicarboxylic acid (12.5 g) and thionyl chloride (50 mL) was refluxed in an atmosphere of nitrogen for 2 hr. The resulting solution was evaporated to yield a solid, 11.2 g. The product, pyridine-2,3-dicarboxylic anhydride, was taken on to the next step without further purification.

A mixture of pyridine-2,3-dicarboxylic anhydride (11.2 g) and phosphorus pentachloride (18.72 g) was heated in a nitrogen atmosphere at 150°C for 6 hr. The mixture was allowed to stand at room temperature overnight. POCI3 formed in the reaction was removed by vacuum distillation, and the desired product was collected when the temperature of distillation reached about 100°C (2 mm Hg). The product was unstable and was stored at -78°C under nitrogen.

Preparation of 9-[2-[M .l-dimethvlethvl.aminol-l-hvdroxvethvi H-

[1.6]benzodioxoninof3.4-b]pvridine-5.13-dione. trifluoroacetic acid salt

(i)

The di-acid chloride, prepared above, (4.18 g), was dissolved in CH₂CI₂ (300 mL), and the solution was cooled to below -70°C in an atmosphere of N_2* In a separate flask was made up a solution of the triol substrate (6.428 g) and 6.28 mL of triethyiamine (NEt3) in CH₂CI₂ (350 mL). This second solution was added dropwise to the first solution over a period of about 21 h. TLC showed that no starting material remained after this time. The organic layer was . washed with satd. NaCI soln., dried over MgS0 , filtered, and evaporated under vacuum to yield a tan solid. The crude product was purified by short-path column chromatography over silica gel, eluting with 10%EtOAc/CH₂Cl2. The product was used in the next step without further purification.

(ϋ)

The product from the previous reaction (0.135 g) was dissolved in CH2CI2 /isopropanol (20 mL; 1 :1 mixture). The solution was added to a hydrogenation flask containing 10% Pd-C which was being flushed with N₂- The suspension was stirred while CF₃C0₂H (24 μl_) was added. The solution was then stirred in an atmosphere of H₂ overnight. The reaction was complete as determined by TLC. The catalyst was removed by filtration, and the solvents were removed by evaporation in a vacuum. The crude product was purified by short-path column chromatography on silica gel using CH₂CI₂ /5% -> 10% MeOH. The product was isolated as a solid, mp 153-155°C. It showed the expected molecular ion for the desired product in the mass spectrum.

EXAMPLE 13

Preparation of 2-f2-fM .1-Dimethvlethvnaminol-1-hvdroxvethvH-7-methvl- 13H-dibenzofb.q rι,5i-dioχonin-6.11-dione. trifluoroacetic acid salt. hemihvdrate. (i)

A solution of triethylamine (3.144 mL) and 4-dimethyl- aminopyridine (DMAP) (410 mg) in dry CH₂CI (150mL) was stirred under nitrogen and cooled in a Dry-Ice/ isopropanol bath. In a dropping funnel attached to the flask were dissolved 4.11 g of the ketone-diol as its HCI salt and triethylamine (2.32 mL) in dry CH CI₂ (200 mL). A solution of 3-methylphthaloyl dichloride (2.7 g) in dry CH₂CI (5 mL) was drawn into a syringe which was then connected to the reaction flask by a needle through a rubber septum. The reagents from the dropping funnel and the syringe were added simultaneously to the cooled reaction flask contents over a period of about 3 hr. The reaction mixture was stored at -78°C overnight. The reaction was worked up by dilution with CH₂CI (300 mL) and washing with water (2 x 200 mL). The organic solution was dried (MgS0₄), filtered, and evaporated under reduced pressure. The crude product was purified on silica gel (250 g of Flash Chromatography Grade) eluting with 5% ethyl acetate/CH CI₂. The desired product from this separation was used in the next step without further purification

(ϋ)

The N-benzyl derivative (0.31 g) from the above reaction was dissolved in 1 :1 isopropanol/CH₂CI₂ (12.4 mL). To this solution was added CF₃COOH (57 μL) and 10% Pd-C catalyst (62 mg). The mixture was hydrogenolyzed at atmospheric pressure for about 28 hr. After filtering off the catalyst, the filtrate was evaporated off and the crude product was purified on Flash Grade silica gel (50 g) in 5% MeOH/CH₂Cl2- ^ThΘ desired product was located by TLC in the fractions eluting from the column. Evaporation led to the product, 197 mg, which showed no sharp melting point, but analyzed correctly:

Found, C, 57.14; H, 5.38; N, 2.66.

Calcd. for C24H26NO7F3O.5 H₂0, C, 56.91 ; H, 5.37; N, 2.76

EXAMPLE 14

Preparation of 8-[2-[M .1-dimethylethyl.amino]-1-hydroxvethvl]- 4H.6H.12H-thienof3.4-c][1.6]b6nzodioxonin-4.12-dione. trifluoroacetate

(i)

A solution of the triol (128 mg), triethylamine (100 μL), and DMAP (10 mg) was made up in CH₂CI₂ (8 mL) at 0°C. To this was added a solution of the di-acid chloride (90 mg) in CH CI₂ (6 mL). The reaction mixture was stirred for 2 hr. at 0°C then it was diluted with CH CI₂ (100 mL). The organic layer was washed with water followed by satd. aqueous NaCI, dried (MgS0₄), and evaporated under reduced pressure to yield the crude product (180 mg) which was used without further purification. (")

The product from the previously described reaction (0.42 g) was dissolved in a mixture of CH₂CI₂/isopropanol (10 mL of 1 :1 ) and was added to a flask containing 10% Pd-C (0.212 g) which was being flushed with N₂. Trifluoroacetic acid (0.369 mL; 5.3 equivs. based on substrate) was added while the suspension was stirred. The stirred mixture was hydrogenated at atmospheric pressure overnight. After about 19 h another batch of catalyst (0.212 g) was added because the reaction was incomplete. Reaction was complete after a further 2.5 h under a hydrogen atmosphere. The catalyst was filtered off and the solvents were removed under vacuum. The residue was kept under high vacuum overnight. The crude product was purified by short-path silica gel chromatography eluting with 10% Me0H/CH₂CI . The desired product was isolated from the eluate and was subjected to a further purification on a second silica gel short-path column. From this column was obtained 0.11 g of the desired ester as a glass which had no definite mp.

Analysis: For C2iH₂2NO7SF3^»0.25 H₂0 CALCD.: C, 51.06; H, 4.59; N, 2.84; S, 6.49 Found: C, 51.08; H, 4.75; N, 2.75; S, 6.15.

EXAMPLE 15 - AEROSOL FORMULATION

A suspension aerosol is made according to the following directions. Disperse a suitable surfactant, such as oleic acid, Span 85 (sorbitan trioleate), oleyl alcohol, sorbitan monooleate, or soy lecithin (10 to 400 mg/ aerosol can) with agitation in an aerosol holding tank maintained at 30°F(-2°C). Add one of the following compounds of this invention

any other compounds of this invention (50 to 400 mg/ aerosol can) in micronized form, and continue agitation. Cover the tank and overlay the concentrated suspension/solution with nitrogen. Run the concentrate into the aerosol cans, fit a valve on each can and crimp onto the can. Finally, charge Freon 12 (dichlorodifluoromethane; 12 to 20 g / aerosol can) through the valve. Propellants other than Freon 12; such as Freon 114 (1 ,2-dichloro-1 ,1 ,2,2-tetrafluoroethane) may be used. Non-Freon propellants may also be used.

PREPARATIVE EXAMPLE 1

A mixture of t-butylacetylchloride (30 g) and paraformaldehyde (6.75 g) was heated under N₂ at 130°C. The original suspension eventually became a clear solution. The reaction was followed by TLC using CH2CI2, visualized with iodine. Reaction was complete after about 72 hr. The crude product was purified by flash chromatography on silica gel eluting with CH2CI2. Evaporation of the fractions containing product yielded 23.3 g of a clear liquid. The product was stored under N in the refrigerator. It was characterized by its ¹H- NMR spectrum which showed the expected two methylene signals (2 X 2H) and a singlet for the t-butyl group (9H).

PREPARATIVE EXAMPLE 2

A mixture of the product from Prep. Example 1 (5 g), potassium iodide (11.6 g) and acetone (250 mL) was stirred under N₂ at room temperature for 2 1/2 days. The mixture was filtered and the red solution retained.

To a solution of α¹-[[(1 ,1-dimethylethyl)phenylmethyl- amino]methyl]-4-hydroxy-1 ,3-benzenedimethanol (9.0 g) in acetone (50 mL), under nitrogen, was added powdered, anhydrous potassium carbonate (2.25 g) and the mixture was stirred for 1 h. at room temperature. The red solution (from above) was added to this suspension over a period of less than 1 minute. Stirring was continued at room temperature. The reaction was followed by TLC (silica gel/ hexane:ethyl acetate 1 :1) until no further changes occurred.

The solids were filtered off, and solvents were removed under vacuum at or below room temperature. The residue was extracted with hexane:ethyl acetate 1 :1 containing some CH2CI2.

The solution was chromatographed on silica gel, eluting with hexane.ethyl acetate 1 :1 to yield 2.5 g of a viscous oil which was stored under N in the freezer. The ¹H-NMR was consistent with the assigned structure.

Analysis: For C27H39NO5; MW 457

FAB-MS; m/e 458 (M+1)

By essentially the same process as that described in Preparative Example 2, the following compound was prepared:

C39H55NO6; FAB-MS; m/e 634 (M+1)

PREPARATIVE EXAMPLE 3

The Product from Preparative Example 2 (8.5 g) was dissolved in dry CH₂CI₂ (255 mL) under N₂ with stirring. The solution was cooled to about -78°C. Triethylamine (2.24 g) was added dropwise over a period of about 30 min. After about 15 min. of additional stirring, distilled o-chlorobenzoyl chloride (3.98 g) in dry CH2CI2 (85 mL) was added to this solution dropwise over a period of about 30 min. The reaction was then kept in a -70°C freezer for 2 1/2 days.

The solvent was removed under high vacuum, the residue was added to a hexane/ethyl acetate mixture (75 mL of 1 :1). A white solid (4.85 g) precipitated out and was filtered off (see later). The solution was evaporated to dryness again and was redissolved in

CH2CI2 : CH3OH (95:5). It was purified first by flash chromatography on silica gel eluting with CH2CI2 : CH3OH (95:5). A second column was run with CH2CI2 : acetone (95:5) to elute a non-polar by-product, followed by CH₂CI₂ : CH3OH (95:5) and CH₂CI₂ : CH3OH (90:10) to elute the desired product. Evaporation of fractions containing the product, as shown by TLC, yielded the desired product (2.33 g).

PREPARATIVE EXAMPLE 4

Chloromethyl pivalate (1.94 mL) was dissolved in dry acetone (120 mL). Potassium iodide (dry; 3.68 g) was added and the reaction was stirred at room temperature for 4 days. The solids were filtered off to produce a clear red solution. To this mixture, which had turned a dark red color, was added anhydrous, powdered potassium carbonate (2.55 g), followed by α¹-[[(1,1-dimethylethyl)phenylmethyl- amino]methyl]-4-hydroxy-1,3-benzenedimethanol (5.13 g). The reaction was followed by TLC until no further changes occurred. The solution had changed color to a pale yellow.

The reaction mixture was filtered and solvent was removed by evaporation under vacuum, and a residue was dissolved in

CH₂CI₂:IPA (96:4; 15 mL). The solution was separated on a silica gel column, eluting with increasing concentrations of IPA in CH₂CI₂. Fractions containing the desired product were evaporated to yield 1.76 g of the desired product as an oil. Characterization was by ¹H-NMR and FAB-MS (Fast Atom Bombardment Mass Spectrometry) which showed m/e 444(m+1 ) as expected for this product.

PREPARATIVE EXAMPLE 5

α¹-[[(1 ,1 -dimethylethyl)phenylmethylamino]methyl]-4- hydroxy-1 ,3-benzenedimethanol (20 g) was dissolved in CH2CI2 (200 mL) and stirred under N2. Triethylamine (16.9 mL was added to the solution. The reaction flask was cooled in an IPA/dry ice bath to -78°C. After 0.25 h, t-butylacetyl chloride (9.3 mL) was added dropwise. The mixture was stirred for 2 h and the reaction was followed by TLC. It was allowed to warm to room temperature (RT) and stirred overnight. Triethylamine (4.2 mL, 0.5 equivs.) was added and stirring was continued at RT until TLC showed that the reaction was complete. The solvents were removed under vacuum, and the product was purified by column chromatography to yield 13.83 g (53%) of the desired product as an oil. It was characterized by FAB-MS; m/e 428 (M+1). PREPARAT»VE EXAMPLE 6

The product from Prep. Example 5 (1.5 g) was dissolved in acetone (dry, 22.5 mL). To this solution was added anhydrous, powdered potassium carbonate (0.58 g) and then very slowly iodomethyl pivalate (23.1 mL containing 3.85 mmol, 10% excess) in a N₂ atmosphere. When the reaction was complete (as determined by TLC) the solids were filtered off and the solvent was removed under reduced pressure. The product was purified by chromatography on the silica gel column eluting with CH₂CI₂:ethyl acetate (9:1). Fractions containing the product were combined and evaporated to yield (0.72 g) of the desired product as a white foam. It was characterized by ¹ H-NMR and FAB-MS; m/e 542 (M+1). PREPARATIVE EXAMPLE 7

O

(CH₃)₃C JL 'O' _^ "Cl

Chloromethyl pivalate (6 mL) was dissolved in dry acetone

(500 mL) in an atmosphere of N2. To the mixture was added dry potassium iodide (15.33 g), and the mixture was stirred at room temperature for two days. After this time the mixture was filtered to yield a clear solution of iodomethyl pivalate. In dry acetone (100 mL), under an atmosphere of N₂, was dissolved α¹-[[(1 ,1 -dimethylethyl)phenylmethylamino]methyl]-4-hydroxy- 1 ,3-benzenedimethanol (10 g), and to the solution was added anhydrous potassium carbonate (5 g). The mixture was stirred for 10 min. then the solution of iodomethyl pivalate (456 mL) was added rapidly at RT. The resulting mixture was stirred for one day at RT.

The solids were filtered off and rinsed with fresh acetone. The combined acetone solutions were evaporated under vacuum to a viscous oil which was redissolved in CH2CI2 (200 mL). This solution was treated with H 0 (300 mL) and the pH of the aqueous phase was adjusted to 7.0 with acetic acid. After separation, the aqueous phase was extracted with CH2CI2 (3 X 200 mL). The combined organic extracts were washed with H2O, dried (MgS04) and evaporated to yield ca. 15 g of crude product mixture. Purification was achieved by column chromatography on silica gel, eluting with 4% IPA in CH2CI2 to yield the desired product (3.6 g) as a clear oil. Characterization was by ¹ H-NMR and FAB-MS; m/e 444 (M+1).

PREPARATIVE EXAMPLE 8

The product of Preparative Example 7 (0.69 g) was dissolved, with stirring, in CH2CI2 (8 mL) in an atmosphere of N2, and the solution was cooled to below -70°C in a Dry-Ice / acetone bath. To the solution was added triethylamine (0.238 mL) and stirring was continued for 15 min. After this time 2,6-dichlorobenzoyl chloride (0.231 mL) was added dropwise by syringe to the cold solution. The reaction was allowed to warm gradually to room temperature and its progress was followed by TLC. After about 4 days an additional quantity of the acid chloride (0.055 mL) was added, and stirring was continued for one more day. The reaction mixture was evaporated to dryness under vacuum to yield a crude mixture which was redissolved in 5% ethyl acetate / CH2CI2 and purified by short-path column chromatography on silica gel, eluting with the same solvent. The desired product was obtained by evaporation of those fractions shown by TLC to contain it. It was obtained as a white foam, 0.93 g, and was characterized by ¹H- NMR.

By essentially the same procedure, with slight modifications well known to one skilled in the art, the following intermediates were prepared:

IH IJ

IM: > / ; IN: (CH₃)₂CHCH₂-; and IP: (CH₃)₃CCH₂- PREPARATIVE EXAMPLE 9

To a solution of the product from Preparative Example 7

(0.6 g) in CH2CI2 (6 mL) was added triethylamine (0.207 mL). The reaction flask was flushed with argon then cooled to below -70°C and kept in an atmosphere of N2. To the cooled solution was added methyl chloroformate (0.11 mL) and the flask was stirred at below -70°C for 4 h. After warming to room temperature the solvent was evaporated under vacuum. The crude product was separated by flash column chromatography on silica gel, eluting with 10% ethyl acetate / CH2CI₂. The desired product was isolated from the relevant fractions, as shown by TLC, by evaporation and used without further purification (see Example 8). It was obtained as a foam, 0.24 g, and was characterized by its ¹ H-NMR spectrum.

PREPARATIVE EXAMPLE 10

The product from Preparative Example 4 (1 g) was dissolved in CH2CI2, under an atmosphere of N2, and was chilled in an IPA / Dry-ice bath to below -70°C. Triethylamine (0.377 mL) was added by syringe, followed by α-furoyl chloride (0.246 mL). The reaction was kept below -70°C overnight then it was followed by TLC. After about 5 days the reaction was essentially complete. The solvents were evaporated off under vacuum, and the crude product was purified by short-path column chromatography, eluting with CH2CI2. The desired product was isolated from the relevant fractions, as shown by TLC, by evaporation under vacuum to yield a clear oil, 0.28 g. Characterization was by ¹ H-NMR. The product was used in the next step without further purification.

By essentially the same procedure, using minor modifications well known to one skilled in the art, the following compound was prepared:

PREPARATIVE EXAMPLE 11

The product from Preparative Example 7 (2.0 g) was dissolved in dry pyridine, under an atmosphere of N , and was treated with di-t-butyldicarbonate (t-BOC anhydride; 1.32 g) at room temperature. The mixture was stirred for 3 days. The reaction mixture was evaporated to dryness under vacuum and the crude product was dissolved in 20% ethyl acetate in hexane. This solution was separated by column chromatography on silica gel, eluting with the same solvent as was used for dissolution of the sample. The product so obtained showed the correct MW by FAB-MS (m/e 544.8; M+1 ) but appeared to contain a trace of impurity. Therefore, it was subjected to a further purification by flash column chromatography on silica gel, eluting with 40% ethyl acetate in hexane. Elution was followed by TLC, and the relevant fractions were combined and evaporated to yield the desired product, 0.83 g, as a yellow oil, which was characterized by its ¹ H-NMR spectrum. It will be apparent to those skilled in the art that in the above examples, and throughout the specification, "Ph" denotes phenyl.

While the present invention has been described in conjunction with the specific embodiments set forth above, many alternatives, modifications and variations thereof will be apparent to those of ordinary skill in the art. All such alternatives, modifications and variations are intended to fall within the spirit and scope of the present invention.

Claims

WHAT IS CLAIMED;

1. A compound selected from the group consisting of:

(A) compounds of the Formula 1(1 ):

wherein: one of R1 and R² represents the group

and the other represents hydrogen or R⁷CO-;

R5 represents Ci to Cβ-alkyl or the group -(CH2)π-Z-(CH2)m-Ar; Z represents O, S or -CH2-; n represents an integer of 1 to 8; m represents zero or an integer of 1 to 8;

R⁷ is C1 to C10 alkyl, C3 to C8 cycloalkyl, aryl, heteroaryi, -N(R9Riθ), ₀r RiiO-; R³, R⁴, R⁹, and R¹⁰ are each independently selected from hydrogen, C1 to C6 alkyl and Ar¹ ;

R⁶ and R¹¹ are each independently C1-C8 alkyl;

Ar and Ar¹ are each independently selected from the group consisting of phenyl or phenyl substituted by one or two substituents selected from the group consisting of, R¹², R¹³0-, R¹⁴S(0)_x-, R¹5CO-, (R16R17)NC0-, F, Cl, Br, I, N0₂, CF₃, CN, or phenyl, wherein x is 0, 1 , or 2;

R¹², R¹³, R¹⁴, R¹⁵, R¹⁶, and R¹⁷ each independently represents an alkyl group having 1 to 6 carbon atoms; (B) Compounds of the Formula 1(2):

wherein:

R5a represents Ci to Cβ-alkyl or the group -(CH₂)_n-Z-(CH₂)m-Ar²;

Z represents O, S or-CH2-; n represents an integer of 1 to 8;

Ar² is selected from the group consisting of phenyl, phenyl substituted by one or two substituents selected from the group consisting of: hydrogen, R ² R¹³0-, R¹⁴S(0)_x-, R15CO-, (R¹6R¹⁷)NCO-, F, Cl, Br, I, NO2, CF3, CN, or phenyl, wherein x is 0, 1 , or 2; or phenyl optionally substituted by two adjacent groups which together form an additional benzenoid ring; m is an integer of from 1 to 8; ring Q represents one of the rings Qi , Q2, Q3 or Q4 below:

X is N or C-R¹⁸; Y is N or C-R²¹; W represents 0 or S; each of R¹⁸, R¹⁹, R²⁰ and R²¹ is independently selected from hydrogen, d-Cβ alkyl, C-i-Cβ alkoxy, Cl, F, Br, I, NO2, CF₃, CN, R²²- S(0)y-, R²³-CO-, (R ⁴R²5)NCO- or phenyl, wherein y is 0, 1 or 2 and each R²², R²³, R²⁴ and R²⁵ is independently C-i-Cβ alkyl, or, in the ring Qi, two adjacent groups which may form together an additional fused benzenoid ring; and

(C) pharmaceutically acceptable acid addition salts thereof.

2. The compound of claim 1 further characterized by said compound being in the form of a pharmaceutically acceptable acid addition salt.

3. The compound of claim 1 or 2 further characterized by

R5 representing iso-C3H7,

or -(CH2)_n-Z-(CH2)m-Ar and R^5a representing iso-C3H7,

or -(CH2)n-Z-(CH2)m-Ar², wherein n and m independently are 2, 3, 4, 5, or 6, Z represents O, and Ar and Ar² are phenyl.

4. The compound of any of claims 1 to 3 further characterized by R¹ representing

and R² representing R⁷-C , R³, R⁴, R⁶ and R⁷ are as defined in claim 1.

5. The compound of any of claims 1 to 3 further characterized by R¹ representing R -CO- and R² representing

_Rβ

wherein R³, R⁴, R⁶ and R⁷ are as defined in claim 1.

6. The compound of any of claims 1 to 5 further characterized by R³ and R⁴ both representing H.

7. The compound of any of claims 1 to 6 further characterized by R⁶ representing C3-C6 alkyl.

8. The compound of any of claims 1 to 7 further characterized by R⁷ representing C1-C6 alkyl, phenyl, substituted phenyl, or unsubstituted heteroaryi.

9. The compound of any of claims 1 to 8 further characterized by R⁷ representing C1-C6 alkyl, phenyl or substituted phenyl.

10. The compound of any of claims 1 to 9 further characterized by Formula 1(1) being a compound of the Formula 1(1'):

11. The compound of any of claims 1 to 3 further characterized by Q representing the ring Qi.

12. The compound of claim 11 further characterized by Q-i representing

wherein X is N or C-R¹⁸, and Y is N or C-R²¹ with the proviso that X and Y are not both N; each of R¹⁸, R¹⁹, R²⁰ and R²¹ is independently selected from hydrogen, C1-C6 alkyl, C1-C6 alkoxy, Cl, F, Br, I, NO₂, CF₃, CN, R²²-S(0)y-, R²³-CO-, (R ⁴R²5)NCO- or phenyl, wherein y is 0, 1 or 2 and each R²², R²³, R²⁴ and R²⁵ is independently C1-C6 alkyl; or in the ring Qi, two adjacent groups may form together an additional fused benzenoid ring.

13. The compound of claims 11 or 12 further characterized by one or two of R¹⁸, R¹⁹, R²⁰ and R²¹ being independently selected from F, Cl, CF3, CH3 and C2H5 and the remainder of these substituents being H.

14. The compound of any of claims 1 to 3 further characterized by Q representing the ring Q2.

15. The compound of any of claims 1 to 3 further characterized by Q representing the ring Q3.

16. The compound of any of claims 1 to 3 further characterized by Q representing the ring Q4.

17. The compound of any of claims 11 to 13 further characterized by Qi being

wherein one of R¹⁹ and R²⁰ is hydrogen and the other is H, F, Cl, C3, CH₃ or C₂H₅.

18. The compound of any of claims 11 to 13 further characterized by Q representing the ring

Qi

and wherein either Y is C-R²¹ and X is N; or X is C-R¹⁸ and Y is N and R¹⁸ and R²¹ are H, F, Cl, CF₃, CH₃ or C H₅.

19. The compound of any of claims 11 to 18 further characterized by having the structural configuration

wherein R^5a and Q are as described in claim 1.

20. The compound of claim 4 or 5 further characterized by having the structural formula

or a pharmaceutically acceptable acid addition salt thereof.

21. The compound of claim 17 further characterized by having the structural formula

NH(CH₂)6-O-(CH 2)₄-phenyl

or a pharmaceutically acceptable acid addition salt thereof.

22. The compound of claim 21 further characterized by having the structural formula

or a pharmaceutically acceptable acid addition salt thereof.

23. The compound of claim 21 further characterized by having the structural configuration

or a pharmaceutically acceptable acid addition salt thereof.

24. The compound of claim 12 further characterized by having the structural formula

or a pharmaceutically acceptable acid addition salt thereof.

25. The compound of claim 20 further characterized by having the structural formula

or a pharmaceutically acceptable acid addition salt thereof.

26. The compound of claim 25 further characterized by having the formula

or a pharmaceutically acceptable acid addition salt thereof.

27. A process for preparing a compound of claim 1 characterized by hydrogenolysis of a compound of Formula

wherein R¹, R², R^5a, and Q are as described in claim 1 , and Ph is phenyl.

28. A pharmaceutical composition, for use in treating asthma, asthmatic bronchitis and other forms of obstructive pulmonary disease, characterized by combining a compound of Formula 1(1 ) or 1(2), as defined in claim 1 , in combination with a pharmaceutically acceptable carrier.

29. A method for treating asthma, asthmatic bronchitis and other forms of obstructive pulmonary disease in a mammal, characterized by administering to said mammal an effective amount of a compound of Formula 1(1 ) or 1(2) as defined in claim 1.

30. The use of a compound of Formula 1(1 ) or 1(2), as defined in claim 1 , for the manufacture of a medicament for use in treating asthma, asthmatic bronchitis and other forms of obstructive pulmonary disease.

31. The use of a compound of Formula 1(1 ) or 1(2), as defined in claim 1 , for the treatment of asthma, asthmatic bronchitis and other forms of obstructive pulmonary disease.

32. A method of preparing a pharmaceutical composition characterized by admixing a compound of Formula 1(1 ) or 1(2), as defined in claim 1 , with a pharmaceutically acceptable carrier.