2,2-DISUBSTITUTED G YCEROL AND GLYCEROL-LIKE COMPOUNDS, COMPOSITIONS AND METHODS OF USE The present invention relates to 2,2- disubstituted glycerol and glycerol-li e compounds, compositions containing such compounds, and methods of using such compounds.

Various publications have disclosed ^' related compounds. For example, the SCRIP PAF REPORT, PJB Publications, 1986 and Ann. Rep Med. Chem. , V20 (1985) Ch. 20 pp 193-202 disclose numerous related compounds synthesized by various researchers. J_^ Med. Chem. Vol. 29, No. 10, pp 1812 to "1814 (1986) and J. Lipid Res. Vol. 28, pp 733 to 738 (1987) disclose related PAF analogs. Similarly, Drugs of the Future, Vol. _12_ (1) p. 14 (1987) discloses numerous related compounds synthesized by a variety of researchers which are related to the compounds described and claimed herein. The following published domestic patents and foreign applications are mentioned therein as disclosing similar compounds:

(a) Japanese Kokai JP 133854, published March 1, 1983;

(b) U.S. Patent 4,504,474 issued December 3, 1985?

(c) British patent application GB 020712, published January 26, 1983, which corresponds to Japanese Kokai J58013592 published on that same date;

(d) German Application DE 133925, published on March 17, 1983;

(e) German Application DE 151378 published on March 2, 1983, corresponding to European Patent Application 72936;

(f) U.S. Patent 4,329,302 issued May 11, 1982;

(g) British patent application GB 020612, published on January 26, 1983;

(h) Japanese Kokai J56 6115 792, published on September 11, 1981;

(i) German Application DT 2752553 published on May 31, 1979;

(j) German Application DT 2009342, published on September 2, 1971;

(k) Japanese Kokai JA 117262, published on September 4, 1980;

(1) German Application DE 151378 published on March 2, 1983 and corresponding to European Patent Application 72936;

(m) German Application DE 3133925 published on March 17, 1983;

(n) German patent applications DE 3,323,833A published on January 1, 1985 and DE 3,209,670A published on September 29, 1983;

(o) European Patent Application EPA 145,303 published on June 19, 1985;

(p) Japanese Kokai J60045518 published March 12, 1985;

(q) European Patent Application EPA138559 published on April 24, 1985;

(r) PCT Application O8504398 published October 10, 1985;

(s) South African Patent Application ZA 8401533A published August 24, 1984;

SUBSTITUTESHEET

(t) Japanese Kokai J58035194 published March 1, 1983; and

(u) Japanese Kokai JP6163617 published April 1, 1986.

SUMMARY OF THE INVENTION The invention described and claimed herein encompasses a compound represented by the formula I

or a pharmaceutically acceptable salt or solvate thereof wherein:

R ¹ is alkyl containing 6 to 22 carbon atoms or -C(0)-D where -D is NR ⁵ R ⁶ , R ⁵ is H or alkyl containing x carbon atoms and R" is alkyl containing y carbon atoms such that the sum of x plus y is an integer of from 1 to 22; when R is alkyl,

R ² is lower alkyl, trifluoromethyl, aralkyl or aryl;

R^ is T-U-V, wherein

T represents

-0-C(0)-0- , -O- , -S- , -NR ^a - , -NR ^a S0 2- , -0-C(0)-NR ^a - or

4 -NR ^a -C(0)-0- wherein R ^a is H, lower alkyl or acyl;

U is -(CH2) _e - wherein e is an integer of from 2

to 10 or where each f is independently

1, 2 or 3, and

V is -A-B, wherein

A is a direct bond, -0-, -S-, -0-(CH ₂ ) _n - where n is 1, 2 or 3, -0-C(0)- or - (R ^a )- where R ^a is as previously defined,

B is alkyl, substituted alkyl, heteroalkyl, substituted heteroalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, heteroaryl, substituted heteroaryl

II _ _h h or -C-N(R ^C ) ₂ where is 0,S or NR ^D , wherein R ^D is H, lower alkyl or CN and each R ^σ is independently H or lower alkyl, such that the group -A-B contains at least one nitrogen atom, and

R ⁴ represents ~ ^x " ^c t> ^H 2b+l ^{wnere D is an} integer of from 1 to 6 and X is methylene, 0, S(0) _c where c is 0, 1 or 2 or

-N(R ^a )- where R ^a is as previously defined, and when R ¹ is -C(0)-D, R ² , R ³ and R ⁴ are as previously defined and T in the definition of R ^J represents n addition to those groups above -0P0 ₃ -.

Preferred compounds falling within the invention include compounds where is -C(0)-D where D is NR ⁵ R ^δ , with preferred values of R ⁵ and R ⁶ being alkyl. Most preferably one of R ⁵ and R ^β is methyl, and the other group is alkyl containing six to nineteen

carbon atoms, most preferably ten to eighteen carbon atoms.

Preferred compounds falling within the invention also include preferred values of R where R ^ώ is lower alkyl, more preferably lower alkyl containing one to three carbon atoms, and most preferably lower alkyl containing one or two carbon atoms.

Preferred compounds of the invention also include compounds having preferred values of T, which include -0-, -0-C(0)-0-, -0-C(0)-NR ^a - and -NR ^a -C(0)-0- where R ^a is preferably H or acyl and most preferably H. The more preferred values of T are -0-, -0-C(0)-NR ^a - and -NR ^a -C(0)-0-, with the most preferred value of T being -0-.

Preferred values of ϋ include -(CH2) _e - and' in particular where e is the integer 4, 5, 6 or 7.

Preferred values of V include -A-B where A is a direct bond, -0- or -NR ^a - wherein R ^a is as previously defined, and B is heteroaryl, heteroalkyl or heterocycloalkyl with heteroaryl being most preferred.

Preferred values of R include those compounds where X is 0 or S(0) _c where c is 0, 1 or 2, with the most preferred value of c being 1 or 2. Most preferably X is 0 and b in the definition of is 1.

Also included are preferred salts of a compound represented by structural formula I including quaternary ammonium compounds, both cyclic and acyclic, the pre¬ ferred cyclic compounds being quaternary ammonium compounds where the ring contains a quaternary nitrogen and the preferred acyclic compounds being quaternary ammonium compounds, quaternized with lower alkyl substituent groups.

The invention further encompasses a pharmaceutical composition comprising a compound repre¬ sented by structural formula I in combination with a pharmaceutically acceptable carrier.

The invention also encompasses a method of treating allergy in a mammal comprising administering to said mammal an antiallergic effective amount of a com¬ pound, represented by structural formula I.

The invention further encompasses a method of treating inflammation in a mammal comprising adminis¬ tering to said mammal an antiinflammatory effective amount of a compound represented by structural formula I.

Preferred species falling within the scope of the invention described and claimed herein are set forth below:

0 CH, II I ³ CH ₂ -0-(CH ₂ ) ₁₅ CH ₃

CH ₂ -O-C N-C ₁₈ H ₃₇ n

CH, C OCH,

(CH ₃ ) _{2 CH} C OCH- 3 i 3 CH.

CH ₂ -0-C-0-(CH ₂ ⁾ ₂ -^-CH3

CH. ,-oJ- ^■ 0-(CH,),-N' S

'2' 2 =

0 CH. 0 CH,

_C H ₂ _0- _C -M-C ₁₈ H ₃₇ n II ! ~-

CH ₂ -0-C-N-C _lg H ₃₇ a C SCK CH, C —OCH, θ

CH,-0-(CH,),-tT s CH ₂ -0-C-NH- (CH _j ) -N (CH ₃ ) -, 0

0 CH, ll i

CH -0-C-N-C _ιg H ₃₇ n ^CH 2-0-C-N(CgH ₁₇ n) ₂

₁₈ „H ₃₇ n

₇ "N _ _/ .

, 2 -CH,SCH

ΓHH ₃ C. OCH, 3 _NH

CH ₂ -0-(CH ₂ )--N S

0 CH, 0 CH. II I II

C .HH ₂ _ ₀ -c-N-C _ιg H ₃₇ n CH ₂ -0-C-N-C _ιg H ₃₇ n

CH. C — OCH, C _ 00CCHH ₃₃

3 i θ CH ₂ NHS0 ₂ (CH ₂ ) ₂ -N?| I-CH ₃ CH. ^■ (CH,).-NH '/ 171

<

0 CH,

II I ³ CH ₂ -0-C-N-C ₁₈ H ₃₇

CH ₃ — C — OCH ₃ CH ₃ C— OCH ₃ _ _χQ I X®

CH, -0-C-NH-(CH,).-N CH NH-C-0- ⁽ CH., ^{) ,} ,-N ⁽ CH ₃ ) ₃

CH ₂ -0- l. ,8H ⁿ ,3-7,n-

CH, — C —OCH, CH ₃ C —OCH

CH ₂ -NHS0 ₂ - (CH ₂ ) ₂ - ^N ^CH ₂ ^" ° ^{" (CH} 2 ^} 7~°~(θJ

O CH, II I CH ₂ -0-C-N-C ₁₈ H ₃ -n

H ₂ -OC(0) -C ₁₈ H ₃₇ n CH,-OC(0)N- ^C 18 ^H 37^ CH, CH.

CH. ^■ OCH. CH. -OCH.

CH ₂ -0-(CH ₂ ) ₇ -NH- l CH ₂ -0- (CH ₂ ι ₇ -N _H Jp

CH.

As used herein, the following terms are used as defined below unless otherwise indicated:

alkyl - represents a straight or branched carbon chain containing from one to twenty carbon atoms, preferably one to eighteen carbon atoms;

lower alkyl - represents a straight or branched carbon chain containing from one to six carbon atoms;

methylene - represents the divalent group -CH2-;

cycloalkyl - represents a saturated carbocyclic ring of from three to seven carbon atoms;

heterocycloalkyl - represents a saturated ring containing from three _p to seven atoms, preferably two to six carbon atoms and 1 to 3 hetero groups selected from -0-, -S- or

heteroalkyl - represents a saturated branched or unbranched chain containing from one to ten carbon atoms and at least one hetero group selected from -0-, -S- or

acyl - represents a group -alkyl-C(O)- or - -cycloalkyl-C(O)- where alkyl, and cycloalkyl are as defined above;

aryl - represents a carbocyclic group containing from 6 to 14 carbon atoms and having at least one aromatic ring ^• (e.g., phenyl) ;

aralkyl - saturated branched or unbranched chain containing 1 to 6 carbon atoms and one or more phenyl substituents (e.g., benzyl);

heteroaryl - represents a 5 or 6 membered aromatic ring containing from 1 to 4 heteroatoms;

halo - means chloro, bromo or fluoro;

substituted aryl and heteroaryl - aryl and heteroaryl as defined above with each substitutable carbon atom being intended as a possible point of substitution with one or more of halo, alkyl, -N(R ^a ) ₂ , -SR ^a , -OR ^a or -C0 ₂ R ^a wherein R ^a is as previously defined, and each substitutable heteroatom being substituted with alkyl, -N(R ^a ) ₂ , -SR ^a , -OR ^a or -C0 ₂ R ^a wherein R ^a is as previously defined;

substituted heterocycloalkyl - heterocycloalkyl as defined above with each substitutable heteroatom or carbon atom being a possible point of substitution with one or more of alkyl, -N(R ^a ) ₂ , -SR ^a , -OR ^a or -C0 ₂ R ^a wherein R ^a is as previously defined. Substituted heterocycloalkyl also includes non-aromatic quaternary ammonium compounds;

substituted alkyl and substituted heteroalkyl - alkyl and heteroalkyl as defined above, with each carbon atom being a possible point of attachment with one or more substituent groups selected from halo, -N(R ^a ) ₂ , -OR ^a , -C0 ₂ R ^a , or -N(R ^a ) ₃ where R ^a is as previously defined, and with each substitutable heteroatom being substituted with -N(R ^a ) ₂ , -OR ^a or -C0 ₂ R ^a .

DESCRIPTION OF THE INVENTION

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

The compounds of the invention of formula I 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.

Certain compounds of the invention are acidic in nature, e.g. those compounds which possess a carboxyl or phenolic hydroxyl group. These compounds may form pharmaceutically acceptable salts. Examples of such salts are the sodium, potassium, calcium, aluminum, gold, copper and silver salts. Also contemplated are salts formed with pharmaceutically acceptable amines such as ammonia, alkyl amines, hydroxyalkylamines, N- meth lglucamine and the like.

Certain basic compounds of the invention are pharmaceutically acceptable salts, e.g., acid addition salts and quaternary ammonium salts. For example, thiazolidinyl nitrogen atoms may form acid addition salts with strong acid. Examples of suitable acids for salt formation are hydrochlo ic, 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. The free base forms may be regenerated by treating the salt with a suitable dilute aqueous base solution such as

dilute aqueous sodium hydroxide, potassium carbonate, ammonia and sodium bicarbonate.

The quaternary ammonium salts are typically prepared by reaction of a tertiary amino group in a compound of formula I with a compound containing a suitable leaving group, such as an alkyl iodide, etc. For example, in the definition of R , where B is substituted heteroalkyl, substituted heterocycloalkyl or substituted heteroaryl, B may contain a quaternary nitrogen. The compounds of the invention which possess an aromatic ring nitrogen atom, as defined above, may also form quaternary ammonium salts at the aromatic ring nitrogen atom. Where A in the definition of V is -0-, or

-S-, and B is heteroalkyl, substituted heteroalkyl, heterocycloalkyl, substituted heterocycloalkyl, heteroaryl or substituted heteroaryl, the heteroatom in the B group is located at any position other than attached to the A group.

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 the invention.

All such acid, base and quaternary salts are intended to be pharmaceutically acceptable salts within the scope of the invention and all acid and base salts are considered equivalent to the free forms of the corresponding compounds for purposes of the invention.

To prepare a compound of the invention the following general reaction scheme may be followed, taking into account the general process description, the reaction scheme and the specific examples contained herein.

Compounds II and III below are conventional starting materials, or may be prepared using conventional methods.

In compound II, and throughout the reaction scheme, R is alkyl, trifluorometh l, aryl or aralkyl.

In compound II where R ² is aryl, said compound may be prepared by conventional methods, taking into account, in particular Searles, et. al., /. Org. Chem. Vol. 24, p. 1839 (1960) where R ² is phenyl. The teachings of Searles are incorporated herein by reference.

In compound III, R° is alkyl containing 6 to 22 carbon atoms, as defined above.

IV

With reference to structural formula I, as represented by formula IV above, R ¹ represents u _fi

-C-NHR° 0 R 1- ¹ - and - ^' C"-NHR°fi are used below interchangably when appropriate. In compound IV above as well as throughout the reaction scheme, when R^ in structural formula I represents hydrogen, R ³ is designated as H. When R ^J is a value other than H, it is designated as R . L as used throughout the general process description designates a leaving group, and P throughout the general process description designates any appropriate protecting group.

IV

VI

o

II

IX CH ₂ 0-C-HHR6

Deprotect R ₂ -C-OC _b H _2b+1

CH ₂ OH

Compound IX may be deprotected, for example, using ethereal hydrochloric acid or alternatively catalytic hydrogenation.

To make compounds of the invention where R in formula I is alkyl, substitute R -L, where L is, e.g., I, Br, CI, tosylate, mesylate, etc., into the reaction with compound II in place of the isocyanate. Compound II may be treated with a strong base, such as NaH, to form an alkoxide, after which the reaction with R -L occurs.

CH2"CCH ₂ 0R ¹

II R ¹ L

IVa

To prepare a compound of the invention containing a 3-ether substituent, (T in the definition of R ^J is -0-) , the following reaction may be utilized.

) _β -0-Si(CH ₃ ) ₂ C(CH ₃ ) ₃

XI

XII

CH ₂ OR ¹

XII R ² 2-C ¹ -R ⁴ 4

Condensation with I H-A-B or A-B CH ₂ 0(CH ₂ ) _e -A-B

XIII

When compound XII is converted to compound XIII, it is treated with an appropriate nucleophilic reagent to displace the mesylate leaving group. The reaction may be run neat or in the presence of inert

solvents, one example of which is dimethylformamide ("DMF") .

When primary or secondary amines are reacted with compound XII above, secondary and tertiary amines are formed in compound XIII, respectively. To prepare a quaternary ammonium compound, a tertiary amine is typically reacted with compound XII. Alternatively, compound XII may be reacted with a primary or secondary amine, and the resulting secondary or tertiary amine may be reacted with a suitable reagent to form a quaternary compound.

To prepare a compound of the invention where ^J contains a phosphate group, i.e. R ³ is T-U-V where

T is -0-P-0-, I

% the following general reaction sequence may be utilized,

POCI3 + -(CH ₂ ) _e OH _^ Cl ₂ P-0-(CH) _e -L XIV

XV

XVI

XVI

XVII

Depending upon the basicity of the -A-B moiety the phosphate group of compound XVII may transfer its hydrogen to the -A-B moiety becoming negatively charged, thereby forming a zwitterionic compound XVII. Zwitterionic forms of the compounds falling within the scope of formula I are included as part of this invention.

To prepare a compound of formula I where carbon atom number 2 in the glycerol backbone is dialkyl substituted, the following general reaction scheme may be utilized. In the reaction scheme, R ⁴ is typically methyl or ethyl, but any other appropriate group could be substituted therefore. R ² and R ⁴ may be the same or different.

o OCH CH3 23 / ^OCH 2 ^CB 3 c c

XXI

XX

The diester XXI may be reduced to the corresponding diol without affecting the R ² and R ⁴ substituents at carbon atom 2.

1) LiAlH ₄ ,LiBH ₄ or ^CH 2 ^0H

XXI Na[AlH^(OCH->CH _? OCH^) _? ] ^ alkyl' —C-alkyl

CH ₂ OH XXII

R ⁶ NCO( l eq) Reflux

0 CH ₂ OCNHR ⁶ CH ₂ OCNHR ⁶ alkyl ^» —C-alkyl Protect \ alkyl • —C-alkyl t p P--τL. ^ ~

CH ₂ OH C J H ₂ 0 ~-P

XXIII xxiv

Af ter protecting the oxygen at carbon atom 3 , the carbamate nitrogen in the side chain attached to carbon atom 1 of the glycerol backbone may be substituted with a group R ⁵ , where R ⁵ is other than hydrogen, and the 3-hydroxy substituent may undergo deprotection.

_χχιv

Phosphorylation of compound XXV may be performed as described with respect to compound X. Alternatively, an alkyl side chain -(CH ₂ ) _e - may be added to the- hydroxyl group at carbon atom 3 to form an ether- as was previously described with respect to compound X.

1) Na© ^€ (Si(CH ₃ ) ₃ ) ₂ CH ₂ OR ¹

2) -{CH ₂ ) _e Si(CH3) ₂ C(CH ₃ )3

XXV alkyl'—C-alkyl

CH ₂ 0(CH ₂ ) _e Si(CH ₃ ) C(CH ₃ ) ₃

XXVI

The silyl protecting group may be removed by conventional means, and the resulting hydroxyalkyl side chain can. be mesylated.

⁽ CH ₃ ⁽ CH ₂ ⁾ 3 ⁾ 4*$-?®-3H ₂ 0 Deprotect

XXVI alkyl'—C-alkyl

CH ₂ 0(CH ₂ ) _e -OH

XXVII

CH ₃ S0 ₂ C1 CH ₂ OR ¹ base solvent

XXVII alkyl'—C-alkyl

I

CH ₂ -0-(CH ₂ ) _e -OS0 ₂ CH3

XXVIII

The mesylate compound XXVIII readily reacts with H-A-B or A-B, to form a compound falling within the scope of formula I.

To make the compounds of the invention where R ⁴ contains a thioether, compound XXX may be treated with base and l-alkylthiosulfonyl-4-methyl benzene to form compound XXXI below.

O _/ OCH2CH3 O^OCH ₂ CH ₃ C 1 ) base

2 ) CH ₃ — ^■ ©> Sθ2 ^sc b ^H 2b-H\ ₎ R ² — t-S-C _b H _2b+1

R ² — C — H

I 0^ ^C ^OCH ₂ CH ₃

O <? ^Q "^OCH CH ₃

XXXI XXX

Compound XXXI may then be reduced at positions 1 and 3, to form a corresponding 1,3-diol.

LiAlH ₄ , LiBH ₄ or CH ₂ OH NaIA1H ₂ (OCH ₂ CH ₂ OCH ₃ ⁾ _1 _R 2 -C-S-Ct _j H^+i

XXXI

CH OH

XXXII

Compound XXXII may be treated with the appropriate alkyl isocyanate under an inert atmosphere, with appropriate heating as necessary. Protection, N- alkylation, and deprotection steps may be performed as appropriate.

XXXII

XXXIII

Protect

ClSi ( CH ₂ ) ₂ C( CH3 } 3

O Di ( isopropyϊ)

II

CH jOCNHR ⁰ ethylamine

CH ₂ OCNR ⁵ R ⁶

_{R 2} 2 _C I-S-C _b H _2b+1 1 ^{R ~C}

CH ₂ -0-Si ( CH ₃ ) ₂ C ( CH ₃ ) 3 «- ^sc b ^H 2b+l

CH ₂ OSi { CH ₃ ) ₂ C ( CH ₃ ) ₃ xxxrv XXXV

Deprotection

XXXVI

The 3-hydroxy compound XXXVI may be alkylated to form compound XXXVII using a protected alkyl chain reagent, which then undergoes deprotection.

1 ⁾ Na© (Si(CH ₃ ) ₃ ) ₂

XXXVI 2 ⁾ Ir-fCHs/g-O-P

XXXVII

XXXVIII

Compound XXXVIII may be subjected to mesylate formation thereby making compound XXXIX, and subsequent mesylate displacement with, H-A-B or A-B as appropriate to form a compound of formula I.

To prepare a compound of formula I where position two of the glycerol backbone is substituted with a sulfoxide or sulfone, the thioether compound XXXIX may be oxidized to the sulfoxide or sulfone using equimolar or an excess amount of metachloroperbenzoic acid (m- CPBA) , respectively.

X I

R ² -

Displacement of the mesylate protecting group may be performed as described above.

To prepare compounds of the invention represented by formula I where T in the definition of R ³ represents -N ^a -S02~, the following modifications to the general reaction scheme may be utilized.

1) iN(Si<CH ₃ ⁾ ₃ ⁾ 2 CH ₂ O

2) R ⁵ - R ² -C-CH ₂ 0-C-NR ⁵ R ⁵

IV

XLV

XLV

XLVII

LVTII

X IX

LI

To prepare compounds falling within the scope of formula I where U in the definition of R ,3- is -(CH ₂ )f "rT i-" ^(CH 2^T" ^{tne f} °l ^lowin g sequence may be utilized. The diol compound LII may be monobrominated in the presence of triphenyl phosphine with carbon tetrabromide and the remaining hydroxy function is protected by silylation.

HO(

Br-(CH ₂ ) _f (CH ₂ ) _f -OSi(CH ₃ ) ₂ C{CH ₃ ) ₃

LIII

Compound LIII may be utilized in a reaction with any appropriately protected .intermediate compound containing a 3-hydroxy group to alkylate said intermediate at position 3.

) _f -O-Si(CH3) ₂ C{CH ₃

LIV

LV

CH9OR ¹

CH ₃ S0 ₂ C1

LV R 2 ² -C'-R4 ⁴ base CH -0-{CH ₂ ) _f —^ (CH ₂ ) _f -OS0 CH ₃

LVI

CHoOR ¹ R 2 ² -C'-R4 ⁴

CH ₂ -C-(CH ₂ )f—£θ) (CH ₂ ) --A-B

LVII

To prepare a compound of the invention where T in the definition of R ³ represents a carbonate moiety, -OCO2-/ a suitable alcohol may first be treated with a strong base to form the anion, then treated with trichloromethyl chloroformate, to yield a compound LVIII.

LVIII

Compound LVIII may then be treated with to yield compound LIX.

LVIII + V-ϋ-0 a®

LIX

By substituting an appropriate primary or secondary amine into the preceding reaction, a carbamate (T = -OC(0)NR ^a -) may be prepared.

LVIII + V-U-NHR ^a

LIX

To prepare the reverse carbamate, the intermediate compound below may be treated with trichloromethyl chloroformate, and the intermediate product LX treated with V-ϋ-O® Na®.

CH ₂ 0R ^J

CH ₂ OK- ^L R 2 ² -C ' -R 4 ⁴

R ² -C-R ⁴ + cι ₃ co-c-cι I CH ₂ NHCOCCl ₃ CH2NH2 O

LX

S OR- R 2 ² -C ' -R 4 ⁴

CH- .NHC-O-U-V V-U-0 a® δ

LX

Compounds LIX and LXI may be alkylated or acylated on the carbamate nitrogen by treating with an appropriate base, such" as NaH-, followed by a suitable alkyating or acylating agent, such as CH _β l and CHr _j C(0)Cl, respectively.

For preparing compounds of the invention where V is A-B and A represents thioether, an appropriate mercapto compound is treated with strong base to form a sulfur anion. The sulfur anion may then be reacted with a mesylate compound, such as compound XII, causing mesylate displacement.

CH ₂ OR ¹

Q XII

HS-B strong S- -B R ² -C-R ⁴ base I

CH ₂ *0-(CH ₂ ) _e -S-B

LXI

Similarly the ester (A = -O-C(O)-) and .the alkyl ether (A = -0-(CH ₂ ) _jj ) may be prepared.

LXIV

LXV

Certain compounds of the invention are prepared from starting materials containing an endo and an exo nitrogen. End products of the invention may therefore contain an exo or endo nitrogen linkage. As used herein, "exo" refers to a nitrogen substituent group, whereas "endo" refers to a nitrogen contained within the ring.

To prepare compounds of the invention where B represents substituted heteroalkyl, the mesylate compound XII is treated with the substituted heteroalkyl containing the desired substitutent, which may be protected, if necessary. The protecting group, if present, is thereafter cleaved to give the compound of the invention.

LXIV

I

If B represents heterocycloalkyl which contains an amino group, compounds where A is a direct bond are prepared as described above from the mesylate intermediate.

If B represents a substituted heterocycloalkyl group, the substituent may or may not require protection, and the protected form of B is used to displace the mesylate intermediate. The compound may then be deprotected to form a compound of the invention.

To make a compound where A is a direct bond and

B represents 11 - C-N(R ^C ) ₂ , the mesylate intermediate XII is displaced with a cyano compound, which is subsequently treated with an alcohol in the presence of acid to form an imino ester, which is then treated with a primary or secondary amine.

The compounds of the invention possess platelet activating factor ("PAF") antagonistic activity. For example, PAF is an important mediator of such processes as platelet aggregation, smooth muscle contraction (especially in lung tissue) , vascular permeability and neutrophil activation. Recent evidence implicates PAF as an underlying factor involved in airway hyperreactivity. The compounds of the invention are therefore useful where PAF is a factor in the disease or disorder. This includes allergic diseases such as asthma, adult respiratory distress syndrome, urticaria and inflammatory diseases such as rheumatoid arthritis and osteoarthritis.

The PAF antagonistic properties of these compounds may be demonstrated by use of standard pharmacological testing procedures as described below. These test procedures are standard tests used to determine PAF antagonistic activity and to evaluate the usefulness of said compounds for counteracting the biological effects of PAF. The in vitro assay is a simple screening test, while the in vivo test mimics clinical use of the compounds described herein.

PAF Antagonism Assay

A. In vitro Assay;

Preparation of platelet-rich plasma (PRP)t Human blood (50 ml) was collected from healthy male donors in an anticoagulant solution (5 ml) containing sodium citrate (3.8%) and dextrose (2%). Blood was centrifuged at 110 X g for 15 min. and the supernatant (PRP) carefully transferred into a polypropylene tube. Platelet-poor- plasma (PPP) was prepared by centrifuging PRP at 12,000 X g for 2 min. (Beckman Microfuge B). PRP was used within 3 hours of drawing the blood.

Platelet Aggregation Assay; When an aggregating agent such as PAF is added to PRP, platelets aggregate. An aggregometer quantifies this aggregation by measuring light transmission through PRP and comparing to PPP. The aggregation assays were performed using a dual-channel aggregometer (Model 440, Chrono-Log Corp., Havertown, PA). PRP (0.45 ml) in aggregometer cuvettes was continually stirred (37°C). Solutions of test compounds or vehicle were added to the PRP, and after incubation for 2 min., 10-15 yl aliquots of PAF solution were added so as to achieve a final concentration of 1-5 X 10 —8°M.

Incubations were continued until the increase in light transmission reached a maximum (usually 2 min). Values

for inhibition were calculated by comparing maximal aggregation obtained in the absence and the presence of the compound. For each experiment, a standard PAF antagonist such as alprazolam was used as a positive internal control. The inhibitory concentration (IC^ _Q ) is the concentration of compound in micromoles at which 50% of the aggregation is inhibited, as measured by the light transmission through each sample of PRP as compared to PPP. The test results are shown below in Table A.

TABLE A

PAF-INDUCED PLATELET AGGREGATION

R I: ; ^' " R ^z R- R" Dose i- Percent Inhibition Notes

rioni

-C(0)NH-C ₁₈ H ₃₇ n_ -CH ₃

CH ₃ ) ₃ -OCH;: 100 100 iodide salt

TABLE A (CONT' D)

PAF-INDUCED PLATELET AGGREGATION

CH ₂ -OR ^J

R ² -C-R ^{4 1} 3

CH -R ^J

R ^α R^ R- Dose ιM Percent Inhibition Notes

-Ci 1 _f i6H ⁿ o33inL -CH ₃ -0C0 ₂ (CH ₂ ) ₂ - ^j -0CH-: 50 32 mesylate

CH~ salt

-C(0)N-C ₁₈ H ₃₇ n_ -CH ₃

TABLE A (CONT'D) PAF-INDUCED PLATELET AGGREGATION

R- ¹ R ^< R ^" R Dose \iΛ Percent Inhibition Notes

50 100

-C(0)N-C ₁₈ H ₃₇ n_ -CH ₃ -0-(CH ₂ ) ₇ -N S -OCH, mesylate

CH, salt

50 100

-C(0)N-C ₁₈ H ₃₇ n_ -CH CHo -O-P-OfCH / -N ^s -OCH. Zwitterionic

CH, form

-C (0)

TABLE A (CONT'D)

PAF-INDUCED PLATELET AGGREGATION

R R' R- Ε Dose vM Percent Inhibition Notes

-(CH ₂ ) ₁₅ CH ₃ -CH ₃ ide

-€(0)

late

TABLE A (CONT'D)

PAF-INDUCED PLATELET AGGREGATION

R ^J R R- R^ Dose \1A Percent Inhibition Notes

Φ

-C(0)N-C ₁₈ H ₃₇ n_ -CH ₃ -0C(0)NH(CH ₂ ) ₂ -N(CH ₃ ) ₃ -OCH ₃ 50 67 chloride CHo salt

-C(0)N-C ₁₈ H ₃₇ n_ -CH ₃ -OC(0)NH(CH ₉ ) -N 5 -OCH, 50 97 iodide

CH, salt

-C(0) late

TABLE A (CONT'D) PAF-INDUCED PLATELET AGGREGATION

R ¹ R ^z R- R ⁴ Dose ι Percent Inhibition Notes

" ^c 16 ^H 33lL ~ ^<Α 3 -0CH ₃ 50 44 iodide salt

late

-C(0) ride

-C(0) -C ₁₈ H ₃₇ n_ -CH, -0-(CH ₂ ) ₇ -NI S -OCH, 50 10 CH _T

R ^J R R-

CH 10 93 iodide θl

-C(0)N-C ₁₈ H ₃₇ j^ -CH ₃ -0(CH ₉ ) ₇ -N ^/ S -OCH, salt

CH, ' \__

-C(0)

TABLE A (CONT'D)

Notes

-C(0)

-C(0) late

TABLE A CONT'D

PAF-INDUCED PLATELET AGGREGATION

R ^* R" R- R Dose j Percent Inhibition Notes

-C(Q)N-C ₁₈ H ₃₇ n_ -CH ₃ -0(CH ) ₇ -N S -S0 ₂ CH ₃ 50 100 mesylate

CH, salt

-C(0)

0 NH ₀ II I ²

-C (0)N-C ₁₈ H _3? n. -CH ₃ -0(CH ₂ ) ₇ -0-C-CH-CH ₂ -SCH ₃ -OCH ₃ 50 28

CH,

TABLE A (CONT'D)

PAF-INDUCED PLATELET AGGREGATION

CHo-OR ¹

2 I 4

R -C-R

C ¹ H^R 3-*

de

-C(0)

-C(0)N-C ₁₈ H _37lL -CH ₃ -NHC0 ₂ (CH ₂ ) ₂ N(CH ₃ ) ₃ -OCH, 50 83 iodide

CH, salt

TABLE A (CONT'D) PAF-INDUCED PLATELET AGGREGATION

R- ¹ R' R~ R" Dose ]H Percent Inhibition Notes -CH ₃ -NHS0 ₂ (CH ₂ ) ₂ -N N -OCH, 50 12

H.

~C(0)N-C ₁₈ H ₃₇ n_ -CH ₃

CH,

PAF is also a known bronchoconstrictive agent in mammals. Hence, PAF antagonism can be evaluated in vivo by measuring inhibition by the compounds of- the invention in PAF-induced bronchoconstriction in guinea pigs.

PAF-Induced Bronchospasm in Guinea Pigs

B. In Vivo Assay

Non-sensitized guinea pigs are fasted overnight, and the following morning are anesthetized with 0.9 ml/kg i.p. of dialurethane (0.1 g/ml of diallybarbituric acid, 0.4 g/ml of ethylurea and 0.4 g/ml of urethane). The trachea is cannulated and the animals are ventilated by a Harvard rodent respirator at 55 strokes/min. with a stroke volume of 4 ml. A side arm to the tracheal cannula is connected to a Harvard pressure transducer to obtain a continuous measure of intratracheal pressure, which is recorded on a Harvard polygraph. The jugular vein is cannulated for the administration of compounds. The animals are challenged i.v. with PAF (0.4 ug/kg in isotonic saline containing 0.25% BSA) and the peak increase in inflation pressure that occurrs within 5 min. after challenge is recorded. Test compounds are administered either orally (2 hrs. prior to PAF as a suspension in 0.4% methylcellulose vehicle) or intravenously (10 min. prior to PAF as a solution in dimethylsulfoxide) .

As may be seen from the data in Table A above, the compounds of formula I are effective PAF antagonists useful for the treatment of allergy and inflammation. The methods of treating allergy and inflammation are part of the invention described herein.

When used for the treatment of allergy, the compounds may be administered by any conventional route of administration in an amount ranging from about 0.001 mg/kg to about 100 mg/kg per day, in single or multiple daily doses.

Similarly, when used for the treatment of inflammation, the compounds may be administered by any conventional route of administration in an amount ranging from about 0.001 mg/kg to about 100 mg/kg per day, in single or multiple daily doses.

For preparing pharmaceutical compositions containing a compound of the invention, inert, pharma¬ ceutically acceptable carriers can be either solid or liquid. Solid form preparations include powders, tablets, dispersible granules, capsules, cachets and suppositories. A solid carrier can be one or more substances which may also act as diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders or tablet disintegrating agents; it can also be an encapsulating material. In powders, the carrier is a finely divided solid which is in admixture with the finely divided active compound. In the tablet the active compound is mixed with a carrier having the necessary binding properties in suitable proportions and compacted in the shape and size desired. The powders and tablets may be comprised of from about 5 to about 70 percent active ingredient. Suitable solid carriers include magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth.

meth lcellulose, sodium carboxymethylcellulose, a low melting wax, cocoa butter and the like. The term "preparation" is intended to include the formulation of the active compound with an encapsulating materiala serving as a carrier, thereby providing a capsule in which the active component (with or without other carriers) is surrounded by the carrier, which is thus in association with it. Similarly, cachets are included. Tablets, powders, cachets and capsules can be used as solid dosage forms suitable for oral administration.

For preparing supposito ies, a low melting wax such as a mixture of fatty acid glycerides or cocoa butter is first melted, and the active ingredient is dispersed homogeneously therein as by stirring. The molten homogeneous mixture is then poured into convenient sized molds, allowed to cool and thereby solidify.

Liquid form preparations include solutions, suspensions and emulsions. As an example may be mentioned water or water-prop lene glycol solutions for parenteral injection. Liquid preparations can also be formulated in solution in polyethylene glycol and/or polypropylene glycol, which may contain water. Aqueous solutions suitable for oral use can be prepared by adding the active component in water and adding suitable colorants, flavors, stabilizing, sweetening, solubilizing and thickening agents as desired. Aqueous suspensions suitable for oral use can be made by dispersing the finely divided active component in water with viscous material, i.e., natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose and other well-known suspending agents.

Liquid form preparations may also include solutions for intranasal administration.

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. Inhalation aerosols may be packaged in a pressure resistant container, which may have a metered dose feature suitable for administration into the oral cavity for inhalation, or into the nasal passageways, thereby delivering a precise amount of aerosol per use.

Also included are solid form preparations which are intended to be converted, shortly before use, to liquid form preparations for either oral or parenteral administration. Such liquid forms include solutions, suspensions and emulsions. These particular solid form preparations are most conveniently provided in unit dose form and as such are used to provide a single liquid dosage unit. Alternately, sufficient solid may be provided so that after conversion to liquid form, multiple individual liquid doses may be obtained by measuring predetermined volumes of the liquid form preparation as with a syringe, teaspoon or other volu'metric container. When multiple liquid doses are so prepared, it is preferred to maintain the unused portion of said liquid doses at low temperature (i.e., under refrigeration) in order to retard possible decomposi¬ tion. The solid form preparations intended to be converted to liquid form may contain, in addition to the active material, flavorants, colorants, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizing agents and the like. The solvent utilized for preparing the liquid form prepara¬ tion may be water, isotonic water, ethanol, glycerine, propylene glycol and the like as well as mixtures thereof. Naturally, the solvent utilized will be chosen with regard to the route of administration, for example, liquid preparations containing large amounts of ethanol are not suitable for parenteral use.

The compounds of the invention may also be deliverable transdermally. The transdermal compositions can take the form of creams, lotions, aerosols and/or emulsions and can be included in a transdermal patch of the matrix or reservoir type as are conventional in the art for this purpose.

Preferably, the pharmaceutical preparation is in unit dosage form. In such form, the preparation is subdivided into unit doses containing appropriate quantities of the active component, e.g., an effective amount to achieve the desired purpose. The unit dosage form can be a packaged preparation, the package containing discrete quantities of preparation, for example, packeted tablets, capsules and powders in vials or ampoules. The unit dosage form can also be a capsule, cachet or tablet itself or it can be the appropriate number of any of these in packaged form. The compositions can, if desired, also contain other therapeutic agents.

The. quantity of active compound in a- unit dose of preparation may b.e varied or adjusted from about 0.001 mg to 1000 mg, more preferably from about 1 mg to 100 mg, according to the particular application.

The actual dosage employed may be varied depending upon the requirements' of the patient and the severity of the condition being treated. Determination of the proper dosage for a particular situation is within the skill of the art. Generally, treatment is initiated with smaller dosages which 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 the invention and the pharmaceutically acceptable salts thereof will be regulated according to the judgement of the attending clinician considering such factors as age, condition and size of the patient as well as severity of the symptom being treated. A typical re¬ commended dosage regimen for oral administration is from 0.25 to 100 mg/day, preferably 10 to 20 mg/day, in two to four divided doses to achieve relief of the symptoms.

PREPARATIVE EXAMPLE 1

DIETHYL-2-ETHYL-2-METHYL MALONATE

Rapidly add a solution of 2-ethyl-diethyl malonate (71.9 g, 0.382 m) and CH ₃ I (47.7 ml, 108.71 g, 0.766 mol) in CH ₂ C1 ₂ (370 ml) to a paddle-stirred solution of tetra n-butyl ammonium sulfate (129.88 g, 0.383 mol) ^' and NaOH (30.60g) in H ₂ 0 (370 ml) at 25 to 40 °C. Stir the system and separate off the CH ₂ C1 ₂ layer.

Rotavap the CH ₂ C1 ₂ layer to give a soft solid. Stir the solid with diethyl ether, filter and rotavap the filtrate to give the title compound in the form of an oil.

Stir the oil with diethyl ether (400 ml) and filter off any solids, washing well with diethyl ether. Dry the filtrate and washings over Na ₂ S0 ₄ and rotavap. High vac dry for 18 hours to yield the title compound as a yellow oil.

PREPARA IVE EXAMPLE 2

2-METHYL-2-ETHYLPROPANE-1, 3-DIOL

Cautiously add a solution of diethyl-2-ethyl-2- methyl malonate (106.8 g , 0.528 mol) in diethyl ether (400 ml) portionwise to a paddle stirred suspension of lithium aluminum hydride (32.71 g, 0.862 mol) in dry diethyl ether (1.4 1) at 22 to 30°C under a N ₂ atmosphere. Stir for 20 minutes at room temperature, then reflux for three hours under N ₂ .

Add Na ₂ SO ₄ *10H ₂ O (100 g) over 45 minutes at 20 to 25°C while under a N ₂ atmosphere with vigorous stirring. Continue stirring for 18 hours to form the title compound as a white suspension.

Filter the suspension and wash the filter cake with diethyl ether. Rotavap the filtrate and washings, and high vac dry to give the title compound as a soft, wax-like solid.

PREPARATIVE EXAMPLE 3

DIETHYL-2-METHYL-2-METHYLTHIOMALONATE

0. sOC —H2„C-H"3 O OCH ₂ CH ₃ I 1) NaH,DMF I

CH —CH 3 i 2) CH ₃ -o>-S0 ₂ SCH ₃ H ₃ —C~ SCH ₃ c OCH ₂ CH ₃ 0^ ^Cχ 0CH ₂ CH ₃

Wash NaH (8.92 g, 0.223 mol) three times with hexanes and once with DMF (230 ml) and place in a 2-liter 3-neck round bottom flask, equipped with a thermometer, dropping funnel, mechanical stirrer and N ₂ inlet/ outlet. Add a solution of diethyl methyl malonate (35.26 g, 0.202 mol) in DMF (108 ml) dropwise over approximately 30 minutes while under nitrogen. Stir for 30 minutes at room temperature and add a solution of methyl thiotosylate (40.93 g, 0.202 mol) in dry DMF (68 ml) dropwise over 7 minutes at 20 to 25°C to form a suspension. Stir for 64 hours at room temperature.

Add H ₂ 0 (125 ml) to the reaction at 22 to 28°C under N ₂ . Pour the reaction mixture into H ₂ 0 (1.2 1) and diethyl ether (300 ml) and stir. Saturate the aqueous layer with NaCl. Separate and extract the aqueous layer with diethyl ether (3 x 150 ml) . -Combine the ether layers and wash with H ₂ 0 (4 x 100 ml) and brine (1 x 180 ml) . Dry over Na ₂ S0^ and rotavap to give the title compound as a clear yellow oil.

PREPARATIVE EXAMPLE 4

2-METHYLTHI0-2-METHYLPR0PANE-1 , 3-DI0L

0 OCH ₂ OH ₃ C CH.OH

CH ₃ — C — SCH ₃ I ² CH ₃ — C— SCH ₃

. ^C \ CH ₂ 0H

0CH ₂ CH ₃

Substitute the title compound of Preparative Example 3 for the 2-ethyl compound in the reaction described in Preparative Example 2 to make the title compound, in the form of a viscous, clear, faintly yellow oil.

PREPARATIVE EXAMPLE 5

2-METHYL-2-PR0PENYL-N-0CTADΞCYLCARBAMATE

CH-

CH- CH,C1 ₉ || 2

II ²

CH,CCH 0H + 0=C= -C _ιa H _{37 i} ^{2 2} _y CH CCH ₂ 0C(0)NH-C ₁₈ H ₇ n

L ₃ vvW ₂ un - ---- ^« -13-37-. heat

Reflux a mixture of 2-methyl-2-propen-l-ol (23.8g, 0.331 mole), n-octadecyl isocyanate (88.7g 0.3 mol) , and methylene chloride (300 ml) for 18 hours. Remove volatiles under reduced pressure and triturate the residual solid thoroughly with acetone (250 ml) at room temperature. Filter to obtain the title compound as a white powder (m.p. 61.5-62.5°C) .

PREPARATIVE EXAMPLE 6

3- (N-0CTADECYLCARBAM0YL)-2-METHYL GLYCEROL

CH ₂ OC(0) H-C ₁₈ H ₃₇ n

+ o _s o ₄ „ _{CH C} _ _0H

³ I

CH ₂ OH

Dissolve osmium tetroxide (3.0g, 0.0118m) in t- butyl hydroperoxide 3 ml and t-butanol (597 ml) . Suspend the title compound of Preparative Example 5 (285g, 0.775m) and t-butyl hydroperoxide (382 ml, 2.79m) along with tetraethylammonium acetate tetrahydrate (57. lg, 0.247m) in acetone (5.7L) and cool to 0°C. Add the

osmiu solution over a period of about 10 minutes. Stir in an ice bath for 2 hours, then at room temperature for 48 hours.

Cool to 0°C, and add a solution of NaHS0 ₃ in water (794g in 4.41L) dropwise, maintaining the temperature at 0°C to 5°C.

Filter off a brownish precipitate, wash the precipitate with water, dissolve in CH ₂ C1 ₂ (6.08L)/CH ₃ OH (3.04L), and wash. Remove solvent and suspend the residue in diethyl ether (1L) . Filter, wash with diethyl ether, and dry to obtain the title compound as a white solid (m.p. 89.5-90.5).

PREPARATIVE EXAMPLE 7 Substitute the compound shown in column one of the Table below for 2-methyl-2-propen-l-ol in the procedure described in Preparative Example 5 above to make the product shown in column two.

TABLE

Reactant Product

PREPARATIVE EXAMPLE 8 Substitute an appropriate reactant olefin disclosed in the Table below into the process of preparative example 6 to make the diol shown in column two.

Table

PREPARATIVE EXAMPLE 9

1-0- (p-ANISYLDIPHENYL)METHYL-2-METHYL-3- (N- OCTADECYLCARBAMOYL)GLYCER0L

Dissolve the title compound of Preparative Example 6 in pyridine (4.05L) and add p-anisyl- chlorodiphenylmethane (277g., 0.397m) . Stir at room temperature until the reactron is complete, as monitored by TLC.

Remove pyridine under reduced pressure. Dissolve the residue in CH ₂ C1 ₂ (3.4L) and wash with H ₂ 0 (twice) and saturated NaCl solution (1.5L) . Dry over Na ₂ S0 ₄ , filter and strip the solvent from the filtrate.

Dissolve the residue in hexane, and chromatograph on silica gel, eluting with hexane-ethyl acetate (4:1) . Combine the appropriate fractions, and concentrate under reduced pressure to obtain the title compound as an off-white solid (68-70°C) .

PREPARATIVE EXAMPLE 10

Substitute the appropriate 2,3-diol from preparative examples 6 and 8 into the reaction described in preparative example 9 above to form the 3-protected hydroxy compound shown below in the table.

Table

Reactant Product

PREPARATIVE EXAMPLE 11

3- (N-METHYL-N-OCTADECYLCARBAMOYL) -2-MΞTHYL- 2-METH0XY-GLYCEROL

Alkylation Step

Rinse NaH with petroleum ether, and suspend NaH in tetrahydrofuran ("THF") (520 ml). Dissolve the title compound of Preparative Example 9 above in THF (2.071) , and add this solution by steady stream over 0.5 hours to the NaH solution. Add THF (1.381) and stir at room temperature for 2.5 hours. Add dropwise a solution of CH ₃ I (239 ml) in THF (690 ml) . Stir at room temperature, and monitor the reaction progress by TLC (hexane-ethyl acetate; 4:1) until starting materials are absent.

Deprotection Step

Cool the reaction mixture to -5°C, and add ethereal hydrochloric acid (648 ml) dropwise over 45 minutes. Stir at -5°C for 0.5 hrs., and monitor reaction progress as before with TLC until the starting material is absent. Concentrate to a residue at room temperature under vacuum. Dissolve the residue in CH ₂ C1 ₂ (3.5L) and wash with H ₂ 0 (4X, 2.3L), then with saturated NaCl solution (2.3L) .

Dry over MgS0 ₄ , filter, wash and strip off the solvent to yield a reddish-amber syrup. Chromatograph on silica gel. Elute with CH C1 ₂ to eliminate less polar impurities at the solvent front, then elute successively with hexane-ethyl acetate (4:1) and hexane-ethyl acetate (2:1). Concentrate the appropriate fractions at • room temperature to yield the title compound as a red-orange solid.

PREPARATIVE EXAMPLE 12 Substitute the reactant shown in column 1 of the Table below for 1-0- (p-anisyl diphenyl) methyl-2-

_* methy1-3- (N-octadeσylcarbamoyl)glycerol in the reaction described -in Preparative Example 11 to prepare the product shown in column 2 below.

TABLE

Reactant Product Notes

PREPARATIVE EXAMPLE 13

3-[7-[ [(1,1-DIMETHYLETHYL)DIMETHYLSILYL]OXY] HEPTYL0XY]-2-METH0XY-2-METHYLPR0PYL-N- METHYLOCTADECYLCARBAMATE

Dissolve the title compound of Preparative Example 11 in DMF (300 ml) and add NaN(Si(CH ₃ ) ₃ ) ₂ (110 ml, 1.0M) in THF with stirring over 8 minutes at 18°C under a atmosphere. Stir at 18°C for 1.5 hours, then add a solution of Br(CH ₂ ) ₇ OSi(CH ₃ ) ₂ C(CH ₃ ) ₃ (34.0 g, 0.11 mmoles) in DMF (100 ml) at 18-22°C. Stir for 1 hr. at room temperature, then heat to 50°C for 18 hrs. Partition the sample between H ₂ 0-diethyl ether.

Concentrate the ether extract on a rotary evaporator. Partition the residue between CH C1 ₂ (500 ml) and H ₂ 0 (250 ml) and separate off the "milky layer". Extract the aqueous layer with CH ₂ C1 ₂ (2x, 250 ml) and combine the organic layers. Wash with H 0 (2x, 150 ml), dry the CH ₂ C1 solution over Na ₂ S0 ₄ , filter and strip the solvent from the filtrate under reduced pressure. Hi-vac dry to give the title compound as a dark amber oil.

PREPARATIVE EXAMPLE 14

Substitute the reactant shown in column 1 of the Table below for 3-(N-methyl-N-octadecylcarbamoyl)-2-

meth l-2-methoxy giycerol in Preparative Examples 13 to make the product shown in column two .

TABLE

- - PREPARATIVE EXAMPLE 15

3-[7- (HYDROXY)HEPTYLOXY] -2-METHOXY-2- METHYLPROPYL-N-METHYLOCTADECYLCARBAMATE

Dissolve the title compound of Preparative Example 13 (59.84g, 0.091 mole max.) in THF. Add (CH ₃ (CH ₂ ) ₃ ) NF*3H ₂ 0 in 3 portions over 10 minutes at 15- 18°C. Stir at room temperature under a N ₂ atmosphere for 3 hrs., and partition between H ₂ 0 and diethyl ether. Monitor reaction progress in the ether layer by TLC.

Concentrate the reaction mixture under reduced pressure and dissolve the residual dark oil in CH ₂ C1 ₂ (300 ml) . Wash (3x) with H ₂ 0, dry over MgS0 ₄ , filter and rotovap filtrate to 150-200 ml. Purify with flash chroma tog raphy on silica gel to yield the title compound.

PREPARATIVE EXAMPLE 16 Substitute a reactant shown below in column 1 of the Table below for 3-[ 7-[ [ (1,1-dimethylethyl) - dimethylsilyl] oxy] heptyloxy-2-methoxy-2-methyl propyl] -N- methyloctadecyl carbamate in Preparative Example 15 to make the compound shown in column 2 below.

TABLΞ

Reactant Product

CH ₂ -OC(0)-N-C ₁₈ H ₃₇ ϋ n CH ₂ -CC (0) N-^gH-^

I CH-o— — CHoCH-3 CH-3 CH *^^ —GrloCH CH-

CH ₂ -0 (CH ₂ ) ₇ -OSi (CH ₃ ) ₂ C (CH ₃ ) ₃ CH ₂ -0(CH ₂ ) ₇ OH

CE ₂ -∞ {Om-C ₁₈ R-- CH ₂ -OC (0) N-C ₁₈ H ₃₇ ⁿ .

CH- ₅ — C— SCH-j CH CH- ₃ - — SCH-j CH-3

CH ₂ -0Si (CH ₃ ) ₂ C (CH ₃ ) ₃ CH ₂ 0H

CH ₂ -OC(0)N-C ₁₈ H ₃₇ ϋ n CH ₂ -CC (0)N-C ₁₈ H ₃₇ ϋ n

C— SCH-3 CH-3 CH- ₃ ~ »— SCH-3 CH,

CH ₂ -0 (CH ₂ ) ₇ 0Si (CH ₃ ) ₂ C (CH ₃ ) ₃ CH ₂ -O(CH ₂ ) ₇ 0H

PREPARATIVE EXAMPLE 17

3-[7-[ (METHANESULFONYL)OXY]HEPTYLOXY]-2-METHOXY- 2-METHYLPROPYL METHYLOCTADECYL CARBAMATE

Add a solution of methanesulfonyl chloride (0.94 g, 8.2 mmoles) in dry benzene (18 ml) to a stirred solution of 3-[7- (hydroxy)heptyloxy]-2-methoxy-2- methylpropyl methyl octadecylcarbamate (4.26 g, 17.8 mmoles) and triethylamine (0.83 g, 8.2 mmoles) in benzene (38 ml) at 5 to 7°C. Stir for 15 min. and warm to room temperature. Dilute with diethyl ether (2x sample volume) after 2 hours, and monitor reaction progress by TLC. If necessary, dilute further with diethyl ether (150 ml), filter off (CH ₃ CH ₂ ) ₃ N ^* HC1, and rotavap filtrate. High vac dry and purify the sample by flash chromatog aphy as necessary to give the title compound as a viscous, slight amber oil.

PREPARATIVE EXAMPLE 18 Substitute a reactant from column 1 of the Table below for 3-[7-(hydroxy)heptyloxy]-2-methoxy-2- methylpropyl-N-methyloctadecylcarbamate in Preparative Example 17 to make the .product shown in column 2 below.

TABLE

- „

CH ₂ -0 (CH ₂ ) ₇ 0H ) ₇ OS0 ₂ CH ₃

PREPARATIVE EXAMPLE 19

3-(N-METHYL)OCTADECYLCARBAMOYLOXY-2-METHOXY-2- METHYLPROPYL-2-BROMOETHYL PHOSPHATE

Step 1

Dissolve -2-bromoethyl phosphochloridate (2.60 g) in CHC1 ₃ (10 ml) ^' and add dropwise to .a mixture of 3- hydroxy-2-methoxy-2-methyl propyl-N-methylocta- decylcarbamate (2.16 g) and triethylamine (2.79 ml) in CHC1 ₃ (50 ml) at 0°C. After complete addition, allow the reaction to come to room temperature, and stir at room temperature for 24 hours. Rotavap in vacuo to give a brown semi solid. Stir with excess diethyl ether and filter. Concentrate the filtrate to give a dark brown oil.

Step 2

Boil the end product of step 1 above in H ₂ 0 (100 ml) and THF (150 ml) for 2 hours. Cool the reaction to room temperature and dilute with diethyl ether. Separate off the ether layer, and extract the aqueous layer repeatedly (3x60 ml) . Combine the ether extracts and dry over Na ₂ S0 . Filter and rotavap in vacuo to give an oil. Redissolve the oil in CHC1 ₃ , dry over Na ₂ S0 ₄ , filter and rotavap. Dry in vacuo to yield the title compound as a brown oil.

PREPARATIVE EXAMPLE 20

1-BR0M0ETHYL-4-[ (1,1-DIMETHYLETHYL)DIMETHYL SI YL]OXYMETHY BENZENΞ

Stir l-bromomethyl-4-hydroxymethyl benzene (20.75 g) in CH ₂ C1 ₂ (300 ml) with diisopropylethylamine (14.01 g) at 18°C, and add a solution of t-butyl dimethyl silyl chloride (16.34 g) in CH ₂ C1 ₂ (100 ml). Stir for one half hour at room temperature, then reflux for 19 hours under a ₂ atmosphere. Monitor reaction progress by TLC.

Rotavap the solution at 30°C, and stir the residual soft solids with hexanes (350 ml). Filter off the solids, washing with hexanes as appropriate. Rotavap

the filtrate and washings at 35°C to give the title compound in crude form as a reddish oil.

PREPARATIVE EXAMPLE 21

3-[ C4-(1,1-DIMETHYLETHYL)DIMETHYLSILYL]OXYMETHYL

PHENYLMETHQXY]-2-METHOXY-2-METHYLPROPYL

N-METHYLOCTADECYLCARBAMATE

(CH ₃ ) ₂ C(CH ₃ ) ₃

Add a solution of sodium bis(trimethyl silyDamide (46.5 ml, l.OM) in THF at 22 to 24°C to a stirred solution of the title compound of Preparative Example 11 in dry dimethylformamide ("DMF") (240 ml) under a N ₂ atmosphere. Stir for 1.5 hours at room temperature. Add a solution of the title compound of Preparative Example 20 in DMF (20 ml) at 21 to 23°C, stir for 1 hour at room temperature, then heat to 50°C and maintain for 3 hours.

Partition the sample between H ₂ 0 and diethyl ether and monitor reaction progress in the ether layer by TLC.

Concentrate the reaction on a rotavap and stir the residue in diethyl ether (400 ml) . Filter through a 3 inch column of Celite. Rotavap the filtrate to give the title compound as an amber oil.

PREPARATIVE EXAMPLE 22

3-[4-(HYDROXYMETHYL)PHENYLMETHOXY]-2-MΞTH0XY-2- METHYLPROPYL-N-METHYLOCTADECYLCARBAMATΞ

Stir the title compound of Preparative Example 21 (31. 89 g) in THF (250 ml) , and while cooling in a water bath , add tetrabutylammonium fluoride ^* 3H 0 rapidly . Continue stirr ing under a N-> atmosphere for 2 hours at room temperature .

Concentrate on the rotavap , partition between H ₂ 0 and diethyl ether (120 ml : 150 ml) and- separate . Extr act the aqueous layer with diethyl ether (2x) and dry the combined ether ^" extracts over Na ₂ S0 ₄ . Filter and rotavap the ^" fi ltrate . Dry the residue under vacuum to obtain a crude form of the title compound as a viscous oil .

The crude product may be purified by flash chroma tog raphy on si lica gel , eluting with acetone- methylene chlor ide ( 1: 9 ) .

PREPARATIVE EXAMPLE 22A

1-HYDROXY- 2-METHYL- 2-METHYLTHIO- 3- (N-METHYL- N-OCTADECYLCARBAMOYLOXY) PROPANE

Substitute the 3-protected alcohol in the reaction described in preparative example 22 to obtain the title compound.

PREPARATIVE EXAMPLE 23

3- [ 4- [ ( METHY LSϋLFONYL) OXYMETHYL] PHENYLMETHOXY] -2- METHOXY-2-METHYLPROPYL-N-METHYLOCTADECYL CARBAMATE

Add a solution of CH ₃ S0 ₂ C1 (0.75 ml, 1.11 g) in benzene (20 ml) to a stirred solution of the title compound of Preparative Example 22 and (CH ₃ CH ₂ ) ₃ N (1.35 ml, 0.98 g) in benzene (50 ml) at 10-12°C. Gradually warm to room temperature and stir for 2.5 hours to obtain the title compound.

After 2.5 hours at room temperature, dilute the reaction mixture with diethyl ether (200 ml) and filter off the side product, (CH ₃ CH ₂ ) ₃ N.HC1, through Celite. Rotavap the filtrate and high vac dry the residue to obtain the title compound in crude form as a viscous- oil.

To purify, flash chro atograph the crude product on silica gel, eluting with acetone-methylene chloride (5:95) . ^*

PREPARATIVE EXAMPLE 24

1-(N-METHYLOCTADECYL)CARBAMQYLOXY-2-METHOXY-2- METHYL-3-(N-(2-CHLOROETHYL)AMINOCARBONYLOXY)PROPANE

CH ₃ —

Combine the title compound of Preparative Example 11 with β-chloroethylisocyanate (0.74 g, 7 mmol) and pyridine (30 ml) and stir at room temperature for 17 hours. Add diethyl ether (100 ml) and wash with ice water (2 X 100 ml) and cold, dilute HCl (3 X 100 ml). Dry over MgS0 ₄ , filter and concentrate to a colorless oil (2.6 g) which is a crude form of the title compound.

Dissolve the crude product in pyridine (40 ml), add β-chloroethylisocyanate (0.5 ml) and stir at room temperature for 66 hours. Add diethyl ether (100 ml) and wash with ice water (3 X 100 ml) and cold dilute HCl (2 X 100 ml). Dry over MgS0 , filter and concentrate to obtain the title compound as a colorless oil.

By substituting an alternative starting material for C1CH ₂ CH ₂ NC(0) , such as C1(CH ₂ ) ₅ NC(0) , longer alkyl chain analogs may be prepared.

PREPARATIVE EXAMPLE 25

l-(N-METHYL0CTADECYL)CARBAMQYL0XY-2-METH0XY-2- METHYL-3-N-(2-I0D0ETHYL)AMIN0CARBQNYL0XYPR0PANE

CH ₂ -0C(0)N-C ₁₈ H ₃₇ n CH ₂ -0C(0)N-C ₁₈ H ₃

CH ₃ —C—OCH H ₃ ^■ + Nal - ► CH —C—OCH ₃ ^CH 3

' . . ., 2—butanone ' „ __ ,„«,,„„„ _ _~ „ CH ₂ -OC(0) HCH ₂ CH ₂ C1 CH ₂ 0C(O)NHCH ₂ CH ₂

Combine the title compound of Preparative Example 24 (1.0 g), Nal (0.8 g) and 2-butanone (15 ml), and reflux under a N atmosphere for 17 hours. Filter off the resulting white solid and rinse with diethyl ether. Concentrate to dryness to obtain a viscous orange oil.

Chromatograph the orange oil on silica gel, eluting with ethyl acetate-CH ₂ Cl ₂ (2:98), to obtain the title compound as a yellow oil, which solidifies to a yellow solid over time.

PREPARATIVE EXAMPLE 26

1-(OCTADECYL-N-METHYL)CARBAMOYLOXY-2-METHOXY-2-

METHYL-3-[(N-2-CHLOROETHYL-N-ACETYL)AMINO-

CARBONYLOXY)]PROPANE

Dissolve the title compound of Preparative Example 24 (0.8 g, 1.5 mmol) in THF (10 ml) under a N ₂ atmosphere, cool to -75°C with acetone and dry ice, and

add LiN(Si(CH ₃ ) ₃ ) ₂ (2 ml). Stir at -78°C for 15 minutes. Add CH ₃ C(0)C1 (0.5 ml) via a syringe and stir at -78°C for about 24 hours.

Add a saturated solution of NaHC0 ₃ (20 ml) and stir for 10 minutes. Extract with diethyl ether (50 ml) and wash successively with diethyl ether, saturated NaHC0 ₃ (20 ml) and H ₂ 0 (30 ml).

Dry over MgS0 , filter and concentrate to yield the title compound as a yellowish oil (1.0 g). Monitor purity with TLC using ethyl acetate-CH ₂ Cl ₂ (1:4).

To further purify, chromatograph the crude product on silica gel, eluting with ethyl acetate-CH ₂ Cl ₂ (1:9).

PREPARATIVE EXAMPLE 27

l-n-HEXADECYL0XY-2-METHYL-2-PR0PENE

CH, Ii 2 CH.,

CH,—C—CH.OH Br(CH ₂ ) ₁₅ CH ₃ KOH/

CH ₃ -C-CH ₂ 0-C ₁₆ H ₃₃ n

Add hexadecyl bromide (20.99 g), 3-hydroxy-2- methyl propene (20.85 g), KOH (14.4 g) and (CH ₃ (CH ₂ ) ₃ ) ₄ N I to dry benzene (200 ml) and heat to reflux, maintaining the reaction under an argon atmosphere with slight positive pressure by balloon. Monitor reaction progress by TLC, using hexane-diethyl ether (9:1).

Cool the reaction and add diethyl ether (75 ml). Wash with IN HCl (2 X 100 ml), saturated NaHC0 ₃ (1 X 150 ml) and brine (2 X 100 ml). Dry over Na ₂ S0 ₄ .

Filter and distill the filtrate to obtain the title compound as a waxy solid (b.p. 182-185°C).

PREPARATIVE EXAMPLE 28

2-(n-HEXADECYLOXYMETHYL)-2-METHYLOXIRA E

Dissolve the title compound of Preparative Example 27 (9.49 g) in CH ₂ C1 ₂ (200 ml) and add m- chloroperbenzoic acid (6.90 g) in portions over 5 min. Monitor reaction progress by TLC using ethyl acetate- hexanes (1:9) .

When reaction is complete, wash the reaction solution with saturated NaHC0 ₃ (2 X 200 ml) , then stir the CH C1 ₂ solution in aqueous 10% NaHS0 ₃ for 20 minutes to form a cloudy white precipitate in the organic layer. Wash the organic layer with satura-ted NaHC0 ₃ (1 X 200 ml) , then with NaOH (IN, 2 X 200 ml) to remove the precipitate. Dry the CH ₂ C1 ₂ solution over MgS0 , filter and concentrate the filtrate to obtain the title compound as a clear oil.

PREPARATIVE EXAMPLE 29

2-METHYL- 2-PR0PENYL-N-METHYL-N-0CTADECYLCARBAMATE

THF

Stir a solution of the title σompund of Preparative Example 5 (18.0. g, 49.0 mmol) in THF (90 ml) and add dropwise over 25 min. lithium

bis(t imeth IsiIyl)amide (1 M, 54 ml) in hexane. Stir the resultant yellow suspension under an inert atmosphere for 25 min, and add dropwise CH I (7.67 g, 54.0 mmol) in THF (15 ml) over 10 min. Stir at room temperature for 25 hours. Add aqueous NH ₄ C1 (2 ml, 6 M) then CH ₂ C1 ₂ (50 ml). Filter through a pad of silica gel, and wash the pad with CH ₂ C1 ₂ (50 ml).

Combine the filtrate and washings and remove the solvent under reduced pressure to yield a residual yellow oil. Chromatograph the residual yellow oil on silica gel, eluting with ethyl acetate-petroleum ether in a stepped gradient (1:24 followed by 1:9) to yield the title compound as an oil.

¹ H NMR (CDC1 ₃ ; δ-values relative to internal TMS) -.

5.00 (br s, 1H), 4.94(br s, 1H), 4.53(s, 2H), 3.29 (br t, 2H), 2.94(s, 3H), 1.78(s, 3H), 1.15-1.6 (complex m, 32H), 0.92(t, 3H).

Mass Spectrum (electron impact): 382[(M+1) ⁺ : 100%],

381[M ⁺ ; 41%]

PREPARATIVE EXAMPLE 30

N-METHYL-N-OCTADECYL CARBAMIC ACID, [(2-METHYL-2-OXIRANYL)METHYL]ESTER

Substitute the title compound of Preparative Example 29 for 0- (n-hexadecylox ) -2-methyl-2-propene in Preparative Example 28 and treat with m-chloroperbenzoic acid as described therein to obtain the title compound as

a colorless oil which solidifies upon standing at room temperature.

¹ H NMR (CDCI3): 4.25 (d, J = 12.5 Hz, 1H) , 3 ^' .96 (d, J = 12.5 Hz, 1H) , 3.26 (t; J = 7.5 Hz, 2H) , 2.90 (s, 3H) , 2.78 (d, J = 5 Hz, 1H) , 2.68 (d, J = 5Hz, 1H) , 1.52 (m, 2H) , 1.38 (s, 3H) , 1.26 (m, 30H) , 0.88 (t, 3H) .

MS (FAB) : 398 [(M+l) ⁺ ; 100%] , 310 (22%), 284 (43%).

PREPARATIVE EXAMPLE 31

1-HEXADECYLOXY- 2-METHYL- 2-METHOXY GLYCEROL

Stir the title compound of Preparative Example 28 in CH ₃ OH (150 ml) , cool to 0°C and add p-toluene- sulfonic acid (200 mg) . Monitor reaction progress by TLC using ethyl acetate-hexanes (1:3).

Concentrate in vacuo and add CHC1 ₃ (200 ml) . Wash with NaHC0 ₃ (10%, 3 x 50 ml) , brine (2 X 50 ml) and dry over MgS0 ₄ . Filter off the drying agent and concentrate the filtrate to yield the title compound in crude form. Separate and purify by flash chroma tog raphy eluting with ethyl acetate-hexanes (1:3).

PREPARATIVE EXAMPLE 32

1-HEXADECYLOXY-2-METHYL-2-METHOXY-3-

CHLOROFORMYLOXYGLYCEROL

CH

Mix the title compound of Preparative Example 31 (0.463 g) with THF (10 ml) at 0°C. Add trichloromethylchloroformate (0.193 ml) at once. Stir for 18 hours under an argon atmosphere, warming to room temperature.

Concentrate the reaction mixture in vacuo to give the title compound as a pale yellow oil.

PREPARATIVE EXAMPLE 33

3-HEXADECYLOXY-2-METHOXY-2-METHYLPROPYL-2- CHLOROETHYL CARBAMATE

^< T ^H 2° ^"C 16 ^H 33^ (o) ? ^H 2~ ^OC 16 ^H 33 ⁿ -

^CH ₃ -C-OCH ₃ H- C1CH ₂ CH ₂ N=C=0 ^ > CH ₃ —C-OCH ₃

^CH 2° ^H CH ₂ OC(0)NHCH ₂ CH ₂ C1

Add the title compound of Preparative Example 31 (0.8345 g) and β-chloroethylisocyanate (0.227 ml) to dry pyridine (25 ml) and stir at room temperature for 17 hours under an argon atmosphere. Concentrate in vacuo to yield the title compound.

Purify the title compound via column σhroma- tography with Merck silica gel (20 g) , eluting with ethyl acetate-hexanes (1:4). Collect the appropriate fractions to obtain the title compound.

PREPARATIVE EXAMPLE 34

3-[l,l-DIMETHYLETHYL)DIMETHYLSILYLOXY]-2-METHYLTHIO- 2-METHYLPROPYL n-OCTADECYL CARBAMATE

₇

CH 3,—

Add t-butyl dimethyl silylchlor ide (13.03 g, 0.0864 mol) in DMF (75 ml) dropwise over 8 minutes to a stirred solution of 3-octadecylcarbamoyloxy-2-methyl-2- methylthio-1-propanol, (37.28 g, 0.0864 mol) and diisopropylethylamine (15.87 ml, 0.0911 g) in DMF (200 ml) at 18°C under a dry N ₂ atmosphere. Stir the solution at room temperature for 3 hours 15 minutes at 32°C. Partition the residue between diethyl ether-H ₂ 0, and monitor reaction progress by TLC, using ethyl acetate- hexanes (1:4) .

Continue stirring as appropriate. Rotavap the reaction mixture to obtain a soft solid.

Flash chromatograph the soft solid loaded as its CH ₂ C1 ₂ solution on a column of silica gel, eluting with ethyl acetate-hexanes (1:9) .

Dry the eluent containing the title compound over Na ₂ S0 ₄ and rotavap to give the title compound as a viscous oil (41.82 g, 89% yield) which solidifies slowly to a white solid (mp 20 - 22°C) .

PREPARATIVE EXAMPLE 35

1- (N-METHYL-N-OCTADECYLCARBAMOYLOXY) - 2-METHYL- 2-METHYLTHIO- 3- (t-BϋTYL DIMETHYL SILY OXY) PROPANE

Treat the 2-methylthio compound from preparative example 34 with sodium hydride and CH ₃ I as described in preparative example 11 to make the title compound in the form of an oil.

PREPARATIVE EXAMPLE 36

1- (N-METHYL-N-OCTADΞCYLCARBAMOYLOXY) -2-METHYL SU LFINYL- 2-METHYL- 3-METHYLSϋ LFONYLOXYHEPTYLOX Y PROPANE

CH ₂ -CC (0) H3 ₁₈ H ₃₇ D. CH ₂ — OC (0)N-C ₁₈ H _3?

CH3-C-SCH3 CH ₃ > CH ₃ -C-S(0)CH ₃ CH ₃

CH ₂ -0 (CH ₂ ) - ^ββQ gEL ₃ CH ₂ -0 (CH ₂ ) - _j OSO-Oϊ-

Stir a solution of the 2-methylthio compound from Preparative Example 18 (1.64 g, 2.57 mmol) and m- chloroperbenzoic acid (.0.47 g, 2.70 mmol) in CH ₂ C1 ₂ (40 ml) at room temperature. Wash with NaHC0 ₃ (1 x 1.1 M) and H ₂ 0 (2x) and dry over MgS0 . Rotavap to give a mixture of the sulf oxide^ sulf ide and sulfone.

The mixture may be rewashed with NaHC0 ₃ (2 x 1.1 m) and H ₂ 0 (IX) , then dried over MgS0 ₄ , rotavaped and high vac dried for 18 hours to yield an amber oil, (1.42 g) which contains the sulfoxide : sulfide (3:1) .

Flash chromatograph on a column of silica gel and elute with ethyl acetate-hexanes (1:2) , and collect the appropriate fractions to obtain the title compound as a mixture of 2 diastereoisomers in the form of an oil.

PREPARATIVE EXAMPLE 37

1- (N-METHYL-N-OCTADECYLCARBAMOYLOXY) -2-METHYL- 2- METHYLSULFONYL-3-METHYLSU LFONYLOXYHEPTYLOX Y PROPANE

Stir a suspension of the 2-methylthio compound of Preparative Example 18 (2.75 g, 0.0043 mol) and m- chloroperbenzoic acid (2.50 g, 0.0145 mol) in CH ₂ C1 ₂ (40 ml) .

After stirring for 18 hours at room temperature, add a further quantity of m-chloroperbenzoic acid (0.82 g, 0.0040 mol) and continue stirring for 5.5 hours.

Wash the reaction mixture with NaHC0 ₃ (3 x 40 ml, 1.1M). and H ₂ 0 (1 x 50 ml) and dry over Na ₂ S0 ₄ . Filter out the drying agent and rotavap the filtrate. Dry the residue in vacuo for 15 hours to obtain the title compound as a viscous oil.

PREPARATIVE EXAMPLE 38

3-DIBENZYLAMIN0-2-HYDR0XY-2-METHYL-l-(N-METHYL-N- OCTADECYLCARBAMOYLOXY)PROPANE

Heat a stirred mixture of the title compound of Preparative Example 30 (8.85 g, 22.3 mmoles) and dibenzylamine (27.9 g, 141 mmoles) to 130°C under an inert atmosphere for 19 hours. Cool the resultant solution to room temperature, and dilute with CH ₂ C1 ₂ (235 ml) and diethyl ether (35 ml) . Stir the solution and add ethereal hydrochloric acid (50 ml, 170 mmoles, 3.4M) . Stir the thick suspension, then filter. Remove solvent from the filtrate under reduced pressure. Redissolve the residual gum in a mixture of diethyl ether (210 ml) and CH ₂ C1 ₂ (115 ml) and wash the resultant solution with saturated brine (150 ml). Filter through anhydrous MgS0 ₄ , remove solvent from the filtrate under reduced pressure, and chromatograph the residual oil on silica gel, eluting with ethyl acetate-hexanes (1:4) to obtain the title compound as an analytically pure oil.

PREPARATIVE EXAMPLE 39

3-DIBENZYLAMINO-2-METHYL-2-METHOXY-l-(N-METHYL-N- OCTADECYLCARBAMOYLOX )PROPANE

CH ₂ -OC(0) -Cι ₈ H ₃₇ ⁿ . CH ₂ -OC(0)N-Cι ₈ H37 ⁿ -

CH ₃ -C-OH CH ₃ NaH x CH3-C-CCH3 CH3

CH ₂ N(CH ₂ -@) ₂ CH3I CH ₂ N(CH ₂ -g)) ₂

Treat the 2-hydroxy compound from the preceding preparative example with NaH and CH ₃ I as described in preparative example 11 to make the title compound in the form of an oil.

¹ H NMR (CDC1 ₃ ): 07.33, 7.29 (m, 10H), 4.08 (d, J = 10 Hz, 1H), 3.96 (d, J = 10 Hz, 1H) , 3.71 (d, J = 13.4 Hz, 1H), 3.59 (d, J = 13.4 Hz), 3.21 (s, 3H), approx. 3.2-3.0 (poorly defined multiplets, approx. 2H), 2.85/2.61 (si broadened singlets, approx. 3H), 1.5-1.4 (br , 2H), 1.25 (m, 30H), 1.21 (s, 3H), 0.88 (t, 3H) .

,MS (FAB): 609 [(M+l) ⁺ ; 99%], 607 [(M-l) ⁺ ; 100%], 531 (27%).

PREPARATIVE EXAMPLE 40

3-AMINO-2-METHOXY-2-METHYL-3-(N-METHYL-N- OCTADECYLCARBAMOYLOXY)PROPANE

0) _c ~C1, _Q 8H3,_7n- ⁿ 3

In a Parr shaker hydrogenation apparatus, combine 3-dibenzylamino-2-hydroxy-2-methyl-l-(N-methyl-N- octadecylcarbamoyloxy)propane from Preparative Example 39 (9.34 g, 15.3 mmoles), glacial acetic acid (0.981 g, 16.4 mmoles), 5% palladium-on-carbon catalyst (1.88 g) and anhydrous ethanol (130 ml). Allow the mixture to shake under 15 p.s.i. hydrogen pressure at room temperature for 110 min. Remove the catalyst by filtration through celite, remove the solvent from the filtrate at reduced pressure, and partition the residue between CH ₂ C1 (150 ml) and a mixture of water (100 ml), brine (50 ml), and 1.1M aqueous sodium bicarbonate (50 ml 1.1 M)). Separate the layers and extract the aqueous phase with CH ₂ C1 ₂ ( 3 X 45 ml). Wash the combined extracts successively with water (100ml) and brine (2 x 150 ml), filter through anhydrous MgS0 , and strip off solvent under reduced pressure. Chromatograph the residual oil. on silica gel, eluting with CH ₂ C1 ₂ -CH 0H (stepped gradient, 95:5 to 90:10 to 78:22), to obtain the title compound as an analytically pure gum (containing 0.2 mole of water).

¹ H NMR (CDC1 ₃ ): δ4.18 (d; J = 10 Hz, IH), 3.98 (d, J = 10 Hz, IH), 3.-3-3.2 (poorly resolved multiplet, 2H), 3.28 (s, 3H), 2.90 (s, 3H), 2.72 (s, 2H), 1.70 (s, un¬ exchangeable, >2H), 1.52 (br m, 2H), 1.27 (m, 30H), 1.17 (s, 3H), 0.89 (t, 3H).

MS (FAB): 429 [(M+l) ⁺ ; 100%].

PREPARATIVE EXAMPLE 41

3-(ETHENYLSULFONYLAMINO)-2-METHOXY-2-METHYLPROPYL-N- METHYL-N-OCTADECYLCARBAMATE

H ₃₇ a _CH3 _

To a stirred mixture of the title compound of Preparative Example 40 (1.0 g, 2.33 mmoles) and (CH ₃ CH ₂ ) ₃ N (283 mg, 2.80 mmoles) in dry THF (15 ml), add a solution of 2-ch oroethanesulfonyl chloride (456 mg, 2.80 mmoles) in 1 ml of dry THF. Stir the resultant mixture under an inert-atmosphere for 4 hours at room temperature. Filter the reaction mixture, concentrate the filtrate under reduced pressure, and partition the residue between ethyl acetate-brine (35 ml:35 ml). Separate the layers and extract the aqueous phase with ethyl acetate (2 X 15 ml). Wash the combined extracts with brine (35 ml), filter through anhydrous MgS0 ₄ , and remove the solvent from the filtrate under reduced pressure. Chromatograph the residual oil on silica gel, eluting with ethyl acetate-hexanes (2:3), to obtain the title compound as an oil which displayed the following spectroscopic properties:

¹ H NMR (CDC1 ₃ ): <S6.54 (dd, J = 10, 17.5 Hz, IH) , 6.23 (d, J = 17.5 Hz, IH), 5.90 (d, J = 10 Hz, IH), 5.01 (br ra, IH), 4.12 (d, J * 11 Hz, IH) , 4.04 (d, J = 11 Hz, IH) , 3.27 (s, 3H), 3.20 (br t, 2H), 3.04 (d, J _<_ 10 Hz, 2H) , 2.90 (br s, 3H), 1.52 (br m, 2H), 1.28 (m, 30H), 1.23 (s, 3H), 0.88 (t, 3H).

MASS SPECTRUM (CHEMICAL IONIZATION): 519 l(M+l ^' ) ⁺ ], 429 (100%); 536 [(M+1+NH ₃ ) ⁺ ] .

PREPARATIVE EXAMPLE 42

2-METHYL-l-N,N-DIOCTYLCARBAMOYLOXY-2-PROPENE

CH.

CH. 0

CH ₃ CCH ₂ OH CH ₃ CCH ₂ OC(0)N(C ₈ H ₁₇ ) ₂ ^C 1-C-N(C ₈ H ₁₇ )

Heat a solution of 2-methyl-2-propen-l-ol (26.0 g; 0.36 mole) and N,N-dioctylchlorocarbonylamine (48.8 g; 0.12 mole; prepared from dioctylamine and trichloromethyl chloroformate by standard methods) in dry tetrahydrofuran (126 mL) under nitrogen at 50°C for 17 h. Add 2-methyl- 2-propen-l-ol (34.6 g; 0.48 mole) and continue heating at 50°C for another- 31 h before introducing a third quantity of the alcohol (8.65 g; 0.36 mole). Heat the reaction mixture under nitrogen at 80°C for another 38 h. Concentrate the mixture under reduced pressure, and flash chromatograph the residue on silica gel, eluting with ethyl acetate-hexane (5:95), to obtain the title compound as an oil.

EXAMPLE 1

3-.7-[3-(N-METHYL-N-OCTADECYLCARBAMOYLOXY)-2-

METHOXY-2-METHYLPROPOXY]HEPTYL]THIAZOLIUM,

METHANESULFONATE, HEMIHYDRATE

CH

Heat a solution of the title compound of Preparative Example 17 (1.46 g, 2.35 mmol), thiazole (5g, 587 mmol) and tetrabutylammonium iodide (43.4 mg, 0.18 mmol) under a ₂ atmosphere at 80°C for 5 hours. Monitor the reaction progress by TLC.

Distill off excess thiazole and dry the residue on a rotavap to yield the title compound as an amber gum. High vac dry the sample to yield the title compound as a brown glass. (1.50g yield). Purify via flash chromatography on silica gel eluting the sample with CH ₂ C1 ₂ -CH ₃ 0H-H 0 (81:18:1). Dry over Na ₂ S0 , rotavap and high vac dry to obtain a white gum.

Further purify the title compound by dissolving in diethyl ether and dry over MgS0 ₄ . Rotavap and high vac dry to obtain a white amorphous solid.

The sample may be dissolved in hexane (7 ml) at -11°C. Filter off a soft, white solid, which melts on warming to room temperature to give a viscous oil. Redissolve the sample in hexane and stir with Darco 660 (0.3g), filter, rotavap and high vac dry to yield an off- white sticky glass. High vac dry over P Ot _j to obtain the title compound as a waxy gum which darkens slightly over time.

EXAMPLE 2

Substitute the appropriate starting material selected from column 1 of table 2 below into the procedure described in Example 1 to make the end product shown in column 2.

TABLE 2

Table 2 (cont.)

Table 2 (cont. )

EXAMPLE 3

3- {4- [ 3- ( N-METHYL-N-QCTADECYLCARBAMQYLOXY ) -2-METHOXY-2- METHYLPROPOXY] BUTYL }THIAZOLIUM , METHAiSlESULFONATE

₃ —

Substitute- silylated bromobutanol for the analogously protected bro oheptanol in the procedure described in preparative -example 13. Deprotect with N CH ₂ CH ₂ CH ₂ CH3) ₄ F ^* 3H ₂ 0, as described in preparative example 15 and mesylate as described in preparative example 17. Introduce thiazole as in Example 1 to obtain the title compound.

EXAMPLE 4

The compounds shown in column 1 of Table 4 below may be debenzylated under a H ₂ atmosphere by treating with Pd on carbon (10%) under standard reaction conditions to synthesize the compounds shown in column two.

TABLE 4

Reactant End Product Notes

CH ₂ -OC(0)N-C ₁₈ H ₃₇ H CH ₂ -OC(O)N-C ₁₈ H ₃₇ L

I CH i-,-— CC—- OOCCHH C CHH-, CH.-C-OCH-, CH-

CH ₂ -0(CH ₂ ) ₇ -N N CH ₂ 0(CH ₂ ) ₇ -N "N

CH ₂ -C-O-CH ₂ ^O> CH ₂ C0 ₂ H

0

EXAMPLE 5

3- (N-METHYL) OCTADECYLCARBAMOYLOXY-2-METHQXY-2- METHYLPROPYL-2-THIAZOLIO ETHYLPHOSPHATE

Combine the title compound of Preparative Example 19 (2.96 g) , thiazole (8.4 g) and tetrabutyl ammonium iodide (1.36g) at room temperature and heat in a preheated oil bath to 120°C for for 2 hours 15 min. Add ether, stir and filter to remove insolubles. Concentrate the filtrate and purify via flash chroma tog raphy on silica gel, eluting with CHC1 ₃ -CH ₃ 0H-H ₂ 0 (65:25:3). Combine the appropriate fractions, rotavap in high vacuo at 30 °C to obtain a sticky brown solid.

Dissolve the sticky brown solid in ethanol, and precipitate with ethyl acetate. Filter to give an off-white hygroscopic solid. Dry in high vacuo at room temperature over P ₂ Oς for 2 days to give the title compound as a bromide salt.

Isolation of Zwitterions

Purify the crude product (0.6g) by flash chroma tog raphy with CHCl ₃ :CH ₃ 0H:H ₂ O (75:24:1) (2X) . Combine the appropriate fractions after the second chroma tog raphy, rotavap in high vacuo at 30 to 35 ^β C, then dry in high vacuo over P ₂ °5 ^ ^{or t o} ^ ^{avs to} obtain the zwitterionic form of the title compound as the monohydrate.

EXAMPLE 6

Following the procedure described above in Example 5, substitute the reactants from column 1 and 2 from table 6 below to make the products shown in column 3.

TABLE 6

SUBSTITUTE SHEET

EXAMPLE 7

3- [ 4- [ 3- (N-METHYL-N-OCTADECYLCARBAMOYLOXY) - 2- METHOXY- 2-METHYL- PROPOXYMETHYL] BENZYL] THIAZOLIUM, METHANESU LFONATE

Heat the title compound of Preparative Example 23 (2.24g) with thiazole (2 ml) at 80°C under a ₂ atmosphere until reaction is complete as monitored by TLC.

Distill off excess thiazole in a water bath (35 to 40°C) , trapping the thiazole with a dry ice trap to yield the title compound in crude form as a tan glass.

To purify, flash chromatograph the title compound with CH C1 ₂ -CH ₃ 0H-H ₂ 0 (80:18:0.25) on a column of silica gel to obtain the title compound as a white waxy solid.

Further purify the white waxy solid by stirring in hexanes (5 ml) and filtering the resulting cloudy solution through medium sintered glass, then washing with additional hexanes .(2 x 3 ml) to obtain a white solid filter cake.

Rotavap the filtrate to obtain the title compound as a viscous oil, which solidifies after high vac drying over P ₂ θ5 (m.p. 33 to 42°C) .

SUBSTITUTESHEET

EXAMPLE 8

3-(7-METHOXY-7,ll-DIMETHYL-4,10-DIOXO-5,9-DIOXA- 3,ll-DIAZANONACOSYL)-THIAZQLIϋM IODIDE, 1 1/2 HYDRATE

Combine the title compound of Preparative Example 25 (0.4g) and thiazole (2.0g) and stir at room temperature for 17 hours, and monitor reaction progress by TLC (CH ₃ 0H-CH ₂ C1 ₂ ; 1:9).

To further purify the compound, stir at 95 to 100°C and monitor by TLC, then chroma tog raph on silica gel (lOOg) , eluting with CH ₂ C1 ₂ (300 ml) , 10% CH ₃ OH in CH ₂ C1 ₂ (200 ml) and H ₂ 0-CH ₃ 0H-CH ₂ C1 ₂ (5:30:100). Dry the appropriate fractions to obtain the title compound as a hygroscopic yellow solid, which may be suspended in diethyl ether and filtered.

EXAMPLE 9

(3-ACETYL-7,ll-DIMETHYL-3,ll-DIAZA-5,9-DIOXA-4,10- DIOXO-7-METHOXYNQNACOS L) PYRIDINIuM CHLORIDE, 1 1/2.

HYDRATE

Reflux a mixture of the title compound of Preparative Example 26 (l.Og) in pyridine (12 ml) for 18

hours under a N ₂ atmosphere. Monitor reaction progress by TLC in ethyl acetate-CH ₂ Cl ₂ (1:4).

Remove pyridine in vacuo and chromatograph the crude product on silica gel, eluting with 5-20% CH3OH- CH ₂ C1 ₂ to obtain the title compound in crude form. Dissolve the crude product in CH ₂ C1 ₂ , filter to obtain a clear yellow solution, and concentrate the filtrate to dryness. Add diethyl ether and concentrate to dryness a second time, to obtain a yellow gummy solid. Dry in a vacuum oven overnight to yield the title compound as the chloride salt.

EXAMPLE 10

1-[2-[ [ [ [2-METHOXY-2-METHYL-3-[ [(N-METHYL-N-

OCTADECYLAMINO)CARBONYL]OXY]PROPYL]OXY]CARBON L]

AMINO]ETHYL]-PYRIDINIUM CHLORIDE, 1-1/2 HYDRATE

Dissolve the title compound of Preparative Example 24 (800 mg) in pyridine (10 ml) and reflux under a N atmosphere for 18 hours. Monitor reaction progress with TLC using CHC1 ₃ -CH ₃ 0H-H ₂ 0 (65:25:4). When reaction is complete, remove the solvent under high vacuum. Chromatograph the residue using TLC grade silica gel (25g) and elute with CH ₃ 0H-CHC1 ₃ (15:85). Remove solvents using a rotavap and add CHCI3 dried over MgS0 ₄ . Filter and remove solvent to yield an oil. Dry in vacuo until the oil solidifies to a waxy solid.

Redissolve the resultant waxy solid in CH ₂ C1 ₂ and dry over MgSO^. Filter and remove the solvent under high vacuum to obtain the title compound as a yellow- green gummy solid.

EXAMPLE 11

(7-METHOXY-7,ll-DIMETHYL-4,10-DIOXO-5,9-DIOXA- 3,11-DIAZANQNAC0SYL)TRIMETHYL AMMONIUM CHLORIDE

Substitute (CH ) ₃ N (3 ml) into the procedure described in Example 10 for pyridine to make the title compound as the chloride salt in the form of a white solid ( .p. partial 110-130°C).

By substituting thiazole for pyridine in the procedure described in example 10, and substituting an alternative starting material in preparative example 24 for β-chloroethylisocyanate, such as CMCH^^ C O) , 6,14- diaza-10,14-dimeth 1-8,2-dioxa-7,13-dioxo-10- methoxydotriacontanylthiazolium is obtained as the chloride salt in the form of a gummy yellow solid.

EXAMPLE 12

3- {7- [3^ ( N-METHYL-N-OCTADECYLCARBAMOYLOXY ) -2- ETHYL-2-METHYLPR0P0XY] HEPTYL }THIAZOLIUM , METHANE SULFONATE , HEMIHYDRATE

Heat the appropriate compound of Preparative Example 18 (694.1 g., 1.12 mmol) and thiazole (2.4g, 28.2 mmol) in solution at 80°C for 22 hours under a N ₂ atmosphere. TLC the reaction mixture to monitor reaction progress.

Distill off excess thiazole at reduced pressure in a water bath, maintaining the temperature at 35°C. Flash chromatograph the residue (602.4 mg) using a column of silica gel, eluting with CH ₂ C1 ₂ -CH ₃ 0H-H ₂ 0 (80:18:0.25).

Dissolve the eluted compound (514.4 mg) in CH ₂ C1 ₂ , dry over MgS0 ₄ , rotavap and high vac dry with a rotavap to give the title compound as a mixture of oil and wax.

EXAMPLE 13

3- {7- [ 3- ( N-METHYL-N-OCTADECYLCARBAMOYLOXY ) -2-

METHYLTHIO-2-METHYLPROPOXY] HEPTYL }THIAZOLIUM ,

METHANESULFONATE

Dissolve the appropriate compound of Preparative Example 18 (1.53g, 2.40 mmol) in thiazole (5.0g, 58.7 mmol) and heat to 80°C for 18 hours under a N ₂ atmosphere.

Distill off the thiazole at 25-30°C under reduced pressure, and dissolve the resulting residue in CH ₂ C1 ₂ . Filter the solution and load the filtrate on a column of silica gel. Flash chromatograph, eluting with

CH ₂ C1^-CH ₃ 0H-H ₂ 0 (81:18:1). Collect the appropriate fractions and evaporate to yield a soft glassy gum.

Dissolve the gum in diethyl ether, filter and rotavap at 28°C. High vac dry the residue. Dissolve the residue in hexanes and high vac dry over P 0^ to form a soft brown wax. Dissolve the sample in CH ₂ C1 ₂ , wash with NaHC0 ₃ solution (2 x 1.1M) and dry to yield the title compound as the 1.25 hydrate.

EXAMPLE 14

Treat the compound shown in column 1 below with thiazole (2 ml, 28.2 mmol) as described in Example 13 to make a compound shown in column two.

EXAMPLE 15

3-{[ {2-(1H-IMIDAZOL-1-YL)ETHYL}SULFQNYL]AMINO }-2- METHOXY-2-METHYLPROPYL METHYL OCTADECYLCARBAMATE

Add imidazole (526 mg, 7.72 mmoles), followed by NaH (61.6 mg, 1.54 mmoles 60%), to a solution of the title compound of Preparative Example 41 (400 mg, 0.772 mmoles) in DMF (12 ml). Stir the resultant mixture for 24 h at room temperature under an inert atmosphere. Filter the reaction mixture, and remove the solvent from the filtrate under reduced pressure. Dissolve the residue in a mixture of CH ₂ C1 ₂ (10 ml) and diethyl ether (15 ml), and wash the solution with a brine (20 ml)-w ^* ater (5 ml) mixture. Back-extract the aqueous layer with two 10-ml volumes of CH ₂ C1 ₂ . Filter the combined extracts through anhydrous MgS0 ₄ , and remove solvent from the filtrate under reduced pressure. Chromatograph the residual oil on silica gel, eluting with CH C1 ₂ -CH 0H (90:10), to obtain the title compound as an analytically pure, slightly sticky solid.

¹ H NMR (CDC1 ₃ ): 67.63 (s, IH) , 7.10 (apparent singlet, IH), 7.00 (apparent singlet, IH), 5.41 (br s, D ₂ 0-exchangeable, IH), 4.47 (t, J = 7.5 Hz, 2H), 4.20 (d, J = 12.5 Hz, IH), 3.95 (d, J = 12.5 Hz, IH), 3.48 (t, J = 7.5 Hz, 2H), 3.3-3.0 (complex m, 4H), 3.26 (s, 3H), 2.90 (two closely spaced peaks, 3H), 1.51

(distorted triplet, 2H), 1.28 (m, 30H), 1.20 (s 3H), 0.90 (t, 3H).

MS (FAB): 587 [(M+l) ⁺ ; 100%] .

EXAMPLE 16

( 4 , 10-DIAZA-6 , 10-DIMETHYL-6-METHOXY-8-OXA-9-OXO- 3-SULFONYLOCTACOSYD-3-METHYL IMIDAZOLIUM METHYLSULFATE

Add dimethyl sulfate (49.4 mg, 0.393 mmoles) to a solution of the title compound of Example 15 (115 mg, 0.196 mmole) in toluene (2 ml). Heat the resultant solution at 50°C. nder an inert atmosphere for two hours. Remove solvent at reduced pressure, and chromatograph the residual oil on silica gel, eluting with CH ₂ :C1 ₂ :CH ₃ 0H:H ₂ 0 (65:25:4), to obtain the title compound as an analytically pure gum.

^L H NMR (CDCI ) : 69.49 (s, IH), 7.60 (br s, IH), 7.26 (br s, IH), 6.46 (br m, IH), 4.76 ( , 2H), 4.2-3.9 (m, 2H), 3.96 (s, 3H), 3.74 (s, 3H), 3.69 (t, J = 6 Hz, 2H), 3.3-3.1 (overlapping multiplets, 4H), 3.27 (s, 3H), 2.89 (s, 3H), 1.51 (m, 2H), 1.27 (m, 30H), 1.23 (s, 3H), 0.88 (t, 3H).

MS (FAB) : 601 (M ⁺ of quaternary cation).

EXAMPLE 17

l-HEXADECYLOXY-2-METHOXY-2-METHYL-3-[ [ [2- (N, -DIMETHYL AMINO) ETHOXY] CARBONYL] OXY] PROPANE

^CH 2°- ^C 16 ^H 33£ ^CH 2-° ^C 16 ^H 332

CH,— C— OCH, (CH ) NCH ₂ CH ₂ OH- ,CH ₃ — C— OCH ₃

CH ₂ -OC0 ₂ CH ₂ CH ₂ N(CH ₃ ) ₂

CH ₂ -OC(0)Cl

Stir the title compound of Preparative Example 32 (0.3242 g) and benzene (5 ml) at 0°C, and add dimethyl aminoethanol (0.088 ml) and (CH ₃ CH ₂ ) ₃ N (20 ml) . Stir the solution for 0.5 hours and concentrate in vacuo. Dilute the solution with pet ether (5 ml) and filter. Wash the filtrate with pet ether (2 X 5 ml) and concentrate to form the title compound as an orange oil.

Separate chromatographiσally using TLC grade silica (40 g) eluting with ethyl acetate-hexanes- (CH ₃ CH ₂ ) ₃ N (25:2:73).

Collect the appropriate fractions and concentrate to obtain the title compound.

By treating the title compound of Example 17 with CH ₃ I under standard reaction conditions, the trimethyl ammonium compound is obtained.

EXAMPLE 18 By substituting the compound shown in column 1 of Table 18 below for dimethylamino ethanol in Example 17 above, the products shown in column 2 are prepared.

SUBSTITUTE SHEET

TABLE

EXAMPLE 19

1-HEXADECYL0XY-2-METHQXY-2-METHYL-3-[ [ [2-(2- METHYLIMIDAZ0L-1-YL)ETH0XY]CARB0NYL]OXY]PROPANE

Mix the bromocarbonate compound from Example 18 with 2-methylimidazole (1.25 eq. ) in 2-butanone (15 ml) and heat to reflux under an argon atmosphere for 18 hours.

Concentrate the reaction in vacuo and purify chromatographically with silica gel (20 g TLC grade), eluting with CHC1 ₃ :CH ₃ 0H ^' (7:3) then CHC1 ₃ :CH ₃ 0H:7+20 (7.0:3.5:0.5) to obtain the title compound as a clear oil.

EXAMPLE 20

l-HEXADECYLOXY-2- ETHOXY-2-METHYL-3-[ [ [2- (2-METHYL-3-N-METHYL-IMIDAZOL-l-YL)ETHOXY]CARBONYL]OXY]-

PROPANE, IODIDE

Stir the title compound from Example 19 (0.2453g, 0.493 mmol) and CH ₃ I (0.046 ml, 0.741 mmol-, 1.5 eq) in dry benzene (15 ml) and heat to reflux for 3

hours . Coll ec t the resultant precip itate in vacuo to obtain the title compound . MS : FAB ( M-Iodine ) 511.

EXAMPLE 21

1-HEXADECYLOXY-2-METHOXY-2-METHYL-3-[ [[2-( ,N- DIMETHYLAMINO)ETHOXY]CARBONYL]OXY]-PROPANE

CH

Substitute pyridine for 2-methylimidazole in the procedure described in Example 19 above to make the title compound as the bromide salt.

EXAMPLE 22

Treat the reactant in column 1 of the table below with CH ₃ I as described in Example 20 to make the product shown in column 2 below.

Reactant Product

EXAMPLE 23

Subst itute the reac tant shown in column 1 below into the procedure descr ibed in Example 10 to make the product shown in column 2 below .

Reactant Product Notes

CH ₂ OC (0)N-C- _L8 H ₃₇ ⁿ -

CH ₃ -C-0CH ₃ CH, Compound in the fo

CH ₂ -NHC0 ₂ CH ₂ CH ₂ C1 of a waxy solid.

EXAMPLE 24

Substitute the appropriate starting material shown below for pyridine in Example 23 above to obtain the product shown below.

Reactant Product Notes

w s CH ₃ - Yellow gummy solid

CH2 C (0) -0-CH ₂ CH ₂ - ^® N _ S Iodide salt

N (CH ₃ ) CH ₃ -C-0CH ₃ Off-white solid

CH ₂ -NC (0) -0-CH ₂ CH ₂ ^® N (CH3) 3 Iodide salt

EXAMPLE 25

7-[2-METHOXY-2-METHYL-3-[(METHYLOCTADECYLCARBAMOYL- OXY)PROPOXY]HEPTYL]-4-THIAZOLIDINECARBOXYLATE

Heat a solution of the title compound of Preparative Example 17 (1.87 g; 3.01 mmole) and R-(-)- thiazolidine-4-carboxylic acid, sodium salt (0.47 gy 3.01 mmole), in 30 mL of dry dimethylsulfoxide under nitrogen at 50°C for 9 h. Pour the reaction mixture into 95 mL of saturated aqueous NaCl and extract with diethyl ether (4 x 50 mL). Wash the combined extracts with water and dry over anhydrous a ₂ SO^. Filter out the drying agent, and remove the solvent from the filtrate under vacuum. Chromatograph the residue on silica gel, eluting with - acetone-methylene chloride (1:9), to obtain the title compound. If necessary, the product thus isolated may be rechromatographed using the same solvent system to obtain the title compound as an analytically pure oil.

EXAMPLE 26

7-[2-METHOXY-2-METHYL-3-[(METHYLOCTADECYLCARBAMOYLOXY)- PROPOXY]HEPTYL]-(2-AMINO-3-METHYLTHIO)PROPIONATE

₃₇ π

-C-CH-CH ₂ SCH,

0

Substitute the sodium salt of S-methyl-L- cysteine for R-(-)-thiazolidine-4-carboxylic acid, sodium salt, in the procedure described in Example 25 to obtain the title compound.

EXAMPLE 27

3-[7-[(3-(PYRIDINYL)OXY]HEPTYLOXY]-2-METHOXY-2- METHYLPROPYL METHYLOCTADECYLCARBAMATE

Heat a mixture of the title compound of Preparative Example 17 (500 mg; 0.804 mmole), 3- hydroxypyridine (380 mg; 3.90 mmoles), and tetrabutylammonium iodide (0.060 mmoles) for 1 hour at 130°C. Filter the reaction mixture through a pad of silica gel, eluting with acetone-methylene chloride-water (100:10:1) to obtain the mesylate salt form of the title compound as a yellow semisolid.

Dissolve the mesylate salt in methylene chloride and wash the solution successively with aqueous sodium bicarbonate, water, and brine. Dry the organic layer over anhydrous sodium sulfate, filter, and concentrate the filtrate under vacuum. Dry the resultant residue in vacuo over phosphorus pentoxide to obtain the free base form of the title compound as a dark green oil.

Dissolve the free base (75 mg; 0.112 mmoles) in 0.5 ml of methylene chloride and add 0.04 mL of 3.4M etheral hydrochloric acid. Stir at room temperature for 5 minutes, remove volatiles and dry over phosphorus

pentoxide under vacuum to obtain the monohydrated hydrochloride acid salt form of the title compound as an analytically pure brown semisolid.

The following formulations exemplify some of the dosage forms of the compositions of this -invention. In each, the term "active compound" designates 3-[7-[3- (2, 3-dihydro-2-imino)thiazol 1]heptylox ]-2-methoxy-2- methylpropyl-N-methyloctadecyl carbamate. It is contemplated, however, that this compound may be replaced by an effective amount of another compound of formula I.

Pharmaceutical Dosage Form Examples

Example A

Tablets

Mix Item Nos. 1 and 2 in a suitable mixer for 10-15 minutes. Granulate the mixture with Item No. 3. Mill the damp granules through a coarse screen (e.g., 1/4") if needed. Dry the damp granules. Screen the dried granules if needed and mix with Item No. 4 and mix for 10-15 minutes. Add Item No. 5 and mix for 1-3 minutes. Compress the mixture to appropriate size and weight on a suitable tablet machine.

Method of Manufacture

Mix Item Nos. 1, 2 and 3 m a suitable blender for 10-15 minutes. Add Item No. 4 and mix for 1-3 minutes. Fill the mixture into suitable two-piece hard gelatin capsules on a suitable encapsulating machine.

Ingredient Active Compound

Add sterile water for injection or bacteriostatic water for injection, for reconstitution.

Example D Injectable

Ingredient mg/ ial

Active Compound 100

Methyl p-hydroxybenzoate 1.8

Propyl p-hydroxybenzoate 0.2

Sodium Bisulfite 3.2

Disodium Edetate 0.1

Sodiu Sulfate 2.6

Water for Injection q.s. ad 1.0 ml

Method of Manufacture (for 1000 vials)

1. Dissolve p-hydroxybenzoate compounds in a portion

(85% of the final volume) of the water for injection at 65-70°C.

2. Cool to 25-35 °C. Charge and dissolve the sodium bisulfite, disodium edetate and sodium sulfate.

3. Charge and dissolve active compound.

4. Bring the solution to final volume by added water for injection.

5. Filter the solution through 0.22 membrane and fill into appropriate containers.

6. Finally sterilize the units by autoclaving.

Example E Nasal Spray

mg/ml

Active Compound 10.0

Phenyl Mercuric Acetate 0.02

Aminoacetic Acid USP 3.7

Sorbitol Solution, USP 57.0

Benzalkoniu Chloride Solution 0.2

Sodium Hydroxide IN Solution to adjust pH

Water Purified USP to make 1.0 ml

Example F Ointment

Formula mg/g

Active Compound 1.0-20.0

Benzyl Alcohol, NF 20.0

Mineral Oil, USP 50.0

White Petrolatum, USP to make 1.0 g

Method of Manufacture

Disperse active compound in a portion of the mineral oil. Mix and heat to 65°C, a weighed quantity of white petrolatum, the remaining mineral oil and benzyl alcohol, and cool to 50°-55°C. with stirring. Add the dispersed active compound to the above mixture with stirring. Cool to room temperature.

Example G Cream

.Formula mg/g

Active Compound 1.0-20.0

Stearic Acid, USP 60.0

Glyceryl Monostearate 100.0

Propylene Glycol, USP 50.0

Polyethylene Sorbitan Monopalmitate 50.0

Sorbitol Solution, USP 30.0

Benzyl Alcohol, NF 10.0 Purified Water, USP to make 1.0 g

Method of Manufacture

Heat the stearic acid, glyceryl monostearate and polyethylene sorbitan monopalmitate to 70°C. In a separate vessel, dissolve sorbital solution, benzyl alcohol, water, and half quantity of propylene glycol and

heat to 70°C. Add the aqueous phase to oil phase with high speed stirring. Dissolve the active compound in remaining quantity of propylene glycol and add to the above emulsion when the temperature of emulsion is 37°- 40°C. Mix uniformly with stirring and cool to room temperature.

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.