DIAMONDOID DERIVATIVES POSSESSING THERAPEUTIC ACTIVITY IN THE

TREATMENT OF VIRAL DISORDERS

BACKGROUND OF THE INVENTION

Field of the Invention

This invention relates to diamondoid derivatives which exhibit anti-viral activity. Specifically, provided are methods of treatment, prevention and inhibition of viral disorders in a subject in need.

State of the Art

Diamondoids are cage-shaped hydrocarbon molecules possessing rigid structures, resembling tiny fragments of a diamond crystal lattice. See Fort, Jr., et al., Adamantane: Consequences of the Diamondoid Structure, Chem. Rev., 64:277-300 (1964). Adamantane is the smallest member of the diamondoid series and consists of one diamond crystal subunit. Diamantane contains two diamond subunits, triamantane contain three, and so on.

Adamantane, which is currently commercially available, has been studied extensively with regard to thermodynamic stability and functionalization, as well as to properties of adamantane containing materials. It has been found that derivatives containing adamantane have certain pharmaceutical uses, including anti-viral properties and uses as blocking agents and protecting groups in biochemical syntheses. For example, α/p/zα-methyl-1- adamantanemethylamine hydrochloride (Flumadine® (remantidine) Forest Pharmaceuticals, Inc.) and 1 -aminoadamantane hydrochloride (Symmetrel® (amantadine) Endo Laboratories, Inc.) may be used to treat influenza. Adamantanes are also useful in the treatment of Parkinson diseases.

However, though research has addressed the application of adamantane derivatives, studies on derivatives of the other two lower diamondoids (diamantane or triamantane) are very limited. U.S. Patent No. 5,576,355 discloses the preparation of adamantane and diamantane alcohol, ketone, ketone derivatives, adamantyl amino acid, quaternary salt or combinations thereof which have antiviral properties. U.S. Patent No. 4,600,782 describes the preparation of substituted spiro[oxazolidine-5,2'-adamantane] compounds useful as antiinflammatory agent. U.S. Patent No. 3,657,273 discloses the preparation of antibiotic adamantane- 1, 3 -dicarboxamides having antibacterial, antifungal, antialgal, antiprotozoal,

and antiinflammatory properties, as well as having analgesic and antihypertensive properties.

New agents, compositions and methods for using these agents and compositions that inhibit and treat viral disorders are needed, which can be used alone or in combination with other agents.

SUMMARY OF THE INVENTION

The present invention provides diamondoid derivatives which exhibit pharmaceutical activity in the treatment, inhibition, and prevention of viral disorders. In particular, the present invention relates to derivatives of diamantane and triamantane, which may be used in the treatment, inhibition, and prevention of viral disorders. Diamantane derivatives within the scope of the present invention include compounds of Formula I and II and triamantane derivatives within the scope of the present invention include compounds of Formula III.

Diamantane derivatives of this invention include a compound of Formula I:

Formula I wherein:

R ¹ , R ² , R ⁵ , R ⁸ , R ⁹ , R ¹² , R ¹⁵ , and R ¹⁶ are independently selected from the group consisting of hydrogen, hydroxy, lower alkyl, substituted lower alkyl, lower alkenyl, alkoxy, amino, nitroso, nitro, halo, cycloalkyl, carboxy, acyloxy, acyl, aminoacyl, and aminocarbonyloxy;

R R ³³ ,, RR ⁴⁴ ,, RR ⁶⁶ ,, R R ⁷ , R ¹⁰ , R ¹¹ , R ¹³ , R ¹⁴ , R ¹⁷ , R ¹⁸ , R ¹⁹ and R ²⁰ are hydrogen; provided that at least two of R ¹ , R ² , R ⁵ , R ⁸ , R ⁹ , R ¹² , R ¹⁵ , and R ¹⁶ are not hydrogen; and that both R ⁵ and R ¹² or R ¹ and R ⁸ are not identical when the remaining of R ¹ , R ² , R ⁸ , R ⁹ , R ¹⁵ , and R ¹⁶ are hydrogen; and pharmaceutically acceptable salts thereof.

In another of its composition aspects, this invention is directed to a compound of Formula I wherein:

R ¹ , R ² , R ⁵ , R ⁸ , R ⁹ , R ¹² , R ¹⁵ , and R ¹⁶ are independently selected from the group consisting of hydrogen, hydroxy, lower alkyl, substituted lower alkyl, lower alkenyl, alkoxy, amino, nitroso, nitro, halo, cycloalkyl, carboxy, acyloxy, acyl, aminoacyl, and aminocarbonyloxy;

R ³ , R ⁴ , R ⁶ , R ⁷ , R ¹⁰ , R ^{1 1} , R ¹³ , R ¹⁴ , R ¹⁷ , R ¹⁸ , R ¹⁹ and R ²⁰ are hydrogen; provided that at least two of R ¹ , R ² , R ⁵ , R ⁸ , R ⁹ , R ¹² , R ¹⁵ , and R ¹⁶ are not hydrogen; and that both R ⁵ and R ¹² are not identical when R ¹ , R ² , R ⁸ , R ⁹ , R ¹⁵ and R ¹⁶ are hydrogen; and that both R ¹ and R ⁸ are not identical when R ² , R ⁵ , R ⁹ , R ¹² , R ¹⁵ and R ¹⁶ are hydrogen; and pharmaceutically acceptable salts thereof.

In one embodiment of the compounds of Formula I, at least three of R ¹ , R ² , R ⁵ , R ⁸ , R ⁹ , R ¹² , R ¹⁵ , and R ¹⁶ are not hydrogen. In another embodiment of the compounds of Formula I, at least four of R ¹ , R ² , R ⁵ , R ⁸ , R ⁹ , R ¹² , R ¹⁵ , and R ¹⁶ are not hydrogen. In yet another embodiment of the compounds of Formula I, five of R ¹ , R ² , R ⁵ , R ⁸ , R ⁹ , R ¹² , R ¹⁵ , and R ¹⁶ are not hydrogen.

In one preferred embodiment of the compounds of Formula I, R ¹ and R ⁵ are aminoacyl and R ² , R ⁸ , R ⁹ , R ¹² , R ¹⁵ , and R ¹⁶ are hydrogen or lower alkyl. In another preferred embodiment of the compounds of Formula I, R ⁵ is amino and two of R ¹ , R ² , R ⁸ and R ¹⁵ are lower alkyl, preferably methyl. In yet another embodiment of the compounds of Formula I, R ⁵ is amino and two of R ¹ , R ² , R ⁸ and R ¹⁵ are lower alkyl. In a preferred embodiment R ¹ and R are methyl and in another preferred embodiment R and R are methyl. In a further embodiment of the compounds of Formula I, R ⁹ or R ¹⁵ is amino and R ¹ is methyl. In another embodiment of the compounds of Formula I, R ² or R ¹⁶ is amino and R ¹ and R ⁸ are methyl.

In another embodiment of the compounds of Formula I, at least one of R ¹ , R ² , R ⁵ , R ⁸ , R ⁹ , R ¹² , R ¹⁵ , and R ¹⁶ is independently selected from the group consisting of amino, nitroso, nitro, and aminoacyl and at least one of the remaining of R ¹ , R ² , R ⁵ , R ⁸ , R ⁹ , R ¹² , R ¹⁵ , and R ¹⁶ are lower alkyl. In a preferred embodiment, at least two of the remaining of R ¹ , R ² , R ⁵ , R ⁸ , R ⁹ , R ¹² , R ¹⁵ , and R ¹⁶ are lower alkyl. In another preferred embodiment, three of the remaining of R ¹ , R ² , R ⁵ , R ⁸ , R ⁹ , R ¹² , R ¹⁵ , and R ¹⁶ are lower alkyl.

In an embodiment of the compounds of Formula I, at least one of R ⁵ and R ¹² is independently selected from the group consisting of amino, nitroso, nitro, and aminoacyl and at least one of R ¹ , R ² , R ⁸ , R ⁹ , R ¹⁵ , and R ¹⁶ is lower alkyl. In a preferred embodiment, at least two of R ¹ , R ² , R ⁸ , R ⁹ , R ¹⁵ , and R ¹⁶ are lower alkyl. In another preferred embodiment, three of R ¹ , R ² , R ⁸ , R ⁹ , R ¹⁵ , and R ¹⁶ are lower alkyl.

In an embodiment of the compounds of Formula I, at least one of R ¹ , R ² , R ⁵ , R ⁸ , R ⁹ , R ¹² , R ¹⁵ , and R ¹⁶ is substituted lower alkyl. In a preferred embodiment, two of R ¹ , R ² , R ⁵ , R ⁸ , R ⁹ , R ¹² , R ¹⁵ , and R ¹⁶ are substituted lower alkyl.

In another embodiment of the compounds of Fomula I, at least one of R ¹ , R ² , R ⁵ , R ⁸ , R ⁹ , R ¹² , R ¹⁵ , and R ¹⁶ is substituted lower alkyl and at least one of the remaining of R ¹ , R ² , R ⁵ , R ⁸ , R ⁹ , R ¹² , R ¹⁵ , and R ¹⁶ are independently selected from the group consisting of amino, nitroso, nitro, and aminoacyl.

Derivatives of diamantane of this invention also include a compound of Formula II:

Formula II wherein:

R ²¹ , R ²² , R ²⁵ , R ²⁸ , R ²⁹ , R ³² , R ³⁵ , and R ³⁶ are independently selected from the group consisting of hydrogen or substituted lower alkyl;

R ²³ , R ²⁴ , R ²⁶ , R ²⁷ , R ³⁰ , R ³¹ , R ³³ , R ³⁴ , R ³⁷ , R ³⁸ , R ³⁹ , and R ⁴⁰ are hydrogen; provided that at least at least one of R ²¹ , R ²² , R ²⁵ , R ²⁸ , R ²⁹ , R ³² , R ³⁵ , and R ³⁶ is substituted lower alkyl; and pharmaceutically acceptable salts thereof.

In a preferred embodiment of the compounds of Formula II, the substituted lower alkyl group is substituted with one substitutent selected from the group consisting of amino, hydroxy, halo, nitroso, nitro, carboxy, acyloxy, acyl, aminoacyl, and aminocarbonyloxy. In a more preferred embodiment of the compounds of Formula II, the substituted lower alkyl

group is substituted with one substituted selected from the group consisting of amino, nitroso, nitro, and aminoacyl.

In one embodiment of the compounds of Formula II, R ²⁵ is substituted lower alkyl and R ²¹ , R ²² , R ²⁸ , R ²⁹ , R ³² , R ³⁵ , and R ³⁶ are hydrogen.

In another embodiment of the compounds of Formula II, R ²⁵ and R ³² are substituted lower alkyl.

In yet another embodiment of the compounds of Formula II, R ²¹ is substituted lower alkyl and R ²² , R ²⁵ , R ²⁸ , R ²⁹ , R ³² , R ³⁵ , and R ³⁶ are hydrogen.

In one embodiment of the compounds of Formula II, R ²⁵ and R ²¹ are substituted lower alkyl.

In another embodiment of the compounds of Formula II, R ³² and R ²¹ are substituted lower alkyl.

Diamantane derivatives of this invention also include a compound having the structure:

or

wherein R is independently hydroxy, carboxy, amino, nitroso, nitro or aminoacyl. In one embodiment of the above compounds, R is hydroxy or carboxy. In another embodiment of the above compounds, R is independently amino, nitroso, nitro or aminoacyl. In a preferred embodiment, R is amino or aminoacyl.

Derivatives of triamantane of this invention include a compound of Formula III:

Formula III wherein:

R ⁴¹ , R ⁴² , R ⁴³ , R ⁴⁶ , R ⁴⁷ , R ⁵⁰ , R ⁵³ , R ⁵⁴ , R ⁵⁵ , and R ⁵⁸ are independently selected from the group consisting of hydrogen, hydroxy, lower alkyl, substituted lower alkyl, lower alkenyl, alkoxy, amino, nitroso, nitro, halo, cycloalkyl, carboxy, acyloxy, acyl, aminoacyl, and aminocarbonyloxy;

R ⁴⁴ , R ⁴⁵ , R ⁴⁸ , R ⁴⁹ , R ⁵¹ , R ⁵² , R ⁵⁶ , R ⁵⁷ , R ⁵⁹ , R ⁶⁰ , R ⁶¹ , R ⁶² , R ⁶³ , and R ⁶⁴ are hydrogen; provided that at least one of R ⁴¹ , R ⁴² , R ⁴³ , R ⁴⁶ , R ⁴⁷ , R ⁵⁰ , R ⁵³ , R ⁵⁴ , R ⁵⁵ , and R ⁵⁸ is not hydrogen; and pharmaceutically acceptable salts thereof.

In one embodiment of the compounds of Formula III, at least two of R ⁴¹ , R ⁴² , R ⁴³ , R ⁴⁶ , R ⁴⁷ , R ⁵⁰ , R ⁵³ , R ⁵⁴ , R ⁵⁵ , and R ⁵⁸ are not hydrogen. In another embodiment of the compounds of Formula III, at least three of R ⁴¹ , R ⁴² , R ⁴³ , R ⁴⁶ , R ⁴⁷ , R ⁵⁰ , R ⁵³ , R ⁵⁴ , R ⁵⁵ , and R ⁵⁸ are not hydrogen. In one embodiment of the compounds of Formula III, R ⁵⁰ is selected from the group consisting of amino, nitroso, nitro, and aminoacyl and at least one of R ⁴¹ , R ⁴ , R ⁴ , R ⁴ , R ⁴⁷ , R ⁵⁰ , R ⁵³ , R ⁵⁴ , R ⁵⁵ , and R ⁵⁸ is lower alkyl. In a preferred embodiment, at least two of R ⁴¹ , R ⁴² , R ⁴³ , R ⁴⁶ , R ⁴⁷ , R ⁵⁰ , R ⁵³ , R ⁵⁴ , R ⁵⁵ , and R ⁵⁸ are lower alkyl.

In one aspect, this invention provides for a method for treating a viral disorder in a subject in need thereof, comprising administering a therapeutically effective amount of a compound of Formula Ia:

Formula Ia wherein:

R ¹ , R ² , R ⁵ , R ⁸ , R ⁹ , R ¹² , R ¹⁵ , and R ¹⁶ are independently selected from the group consisting of hydrogen, hydroxy, lower alkyl, substituted lower alkyl, lower alkenyl, alkoxy, amino, nitroso, nitro, halo, cycloalkyl, carboxy, acyloxy, acyl, aminoacyl, and aminocarbonyloxy;

R ³ , R ⁴ , R ⁶ , R ⁷ , R ¹⁰ , R", R ¹³ , R ¹⁴ , R ¹⁷ , R ¹⁸ , R ¹⁹ and R ²⁰ are hydrogen; provided that at least one of R ¹ , R ² , R ⁵ , R ⁸ , R ⁹ , R ¹² , R ¹⁵ , and R ¹⁶ are not hydrogen; and pharmaceutically acceptable salts thereof. In one embodiment of the compounds of Formula Ia, at least two of R ¹ , R ² , R ⁵ , R ⁸ , R ⁹ ,

R ¹² , R ¹⁵ , and R ¹⁶ are not hydrogen. In another embodiment of the compounds of Formula Ia, at least three of R ¹ , R ² , R ⁵ , R ⁸ , R ⁹ , R ¹² , R ¹⁵ , and R ¹⁶ are not hydrogen. In another embodiment of the compounds of Formula I, at least four of R ¹ , R ² , R ⁵ , R ⁸ , R ⁹ , R ¹² , R ¹⁵ , and R ¹⁶ are not hydrogen. In yet another embodiment of the compounds of Formula I, five of R ¹ , R ² , R ⁵ , R ⁸ , R ⁹ , R ¹² , R ¹⁵ , and R ¹⁶ are not hydrogen.

In another embodiment of the compounds of Formula Ia, R ¹ and R ⁵ are aminoacyl and R ² , R ⁸ , R ⁹ , R ¹² , R ¹⁵ , and R ¹⁶ are hydrogen or lower alkyl. In another preferred embodiment of the compounds of Formula Ia R ⁵ is amino and two of R ¹ , R ² , R ⁸ and R ¹⁵ are lower alkyl, preferably methyl. In yet another embodiment of the compounds of Formula Ia R ⁵ is amino and two of R ¹ , R ² , R ⁸ and R ¹⁵ are lower alkyl. In a further embodiment of the compounds of Formula Ia, R ⁹ or R ¹⁵ is amino and R ¹ is methyl. In another embodiment of the compounds of Formula Ia, R ² is amino, R ¹ is methyl, and R ⁸ or R ¹⁵ is methyl.

In another embodiment of the compounds of Formula Ia, at least one of R ¹ , R ² , R ⁵ , R ⁸ , R ⁹ , R ¹² , R ¹⁵ , and R ¹⁶ is independently selected from the group consisting of amino, nitroso, nitro, and aminoacyl and at least one of the remaining of R ¹ , R ² , R ⁵ , R ⁸ , R ⁹ , R ¹² , R ¹⁵ , and R ¹⁶ are lower alkyl. In a preferred embodiment, at least two of the remaining of R , R , R , R ,

R ⁹ , R ¹² , R ¹⁵ , and R ¹⁶ are lower alkyl. In another preferred embodiment, three of the remaining of R ¹ , R ² , R ⁵ , R ⁸ , R ⁹ , R ¹² , R ¹⁵ , and R ¹⁶ are lower alkyl.

In one embodiment of the compounds of Formula Ia, at least one of R ⁵ and R ¹² is independently selected from the group consisting of amino, nitroso, nitro, and aminoacyl and at least one of R ¹ , R ² , R ⁸ , R ⁹ , R ¹⁵ , and R ¹⁶ is lower alkyl. In a preferred embodiment, at least two of R ¹ , R ² , R ⁸ , R ⁹ , R ¹⁵ , and R ¹⁶ are lower alkyl. In another preferred embodiment, three of

R ¹ , R ² , R ⁸ , R ⁹ , R ¹⁵ , and R ¹⁶ are lower alkyl.

In one embodiment of the compounds of Formula Ia, at least one of R ¹ , R ² , R ⁵ , R ⁸ ,

R ⁹ , R ¹² , R ¹⁵ , and R ¹⁶ is substituted lower alkyl. In a preferred embodiment, two of R ¹ , R ² , R ⁵ , R ⁸ , R ⁹ , R ¹² , R ¹⁵ , and R ¹⁶ are substituted lower alkyl. In another preferred embodiment, R ⁵ is substituted lower alkyl and R ¹ , R ² , R ⁸ , R ⁹ , R ¹² , R ¹⁵ , and R ¹⁶ are hydrogen. In yet another preferred embodiment, R ⁵ and R ¹² are substituted lower alkyl. In another preferred embodiment, R ¹ is substituted lower alkyl and R ² , R ⁵ , R ⁸ , R ⁹ , R ¹² , R ¹⁵ , and R ¹⁶ are hydrogen.

In yet another preferred embodiment, R ⁵ and R ¹ are substituted lower alkyl. In another embodiment, R ¹² and R ¹ are substituted lower alkyl.

In one embodiment of the compounds of Formula Ia, at least one of R , R , R , R , R ⁹ , R ¹² , R ¹⁵ , and R ¹⁶ is substituted lower alkyl and at least one of the remaining of R ¹ , R ² , R ⁵ , R ⁸ , R ⁹ , R ¹² , R ¹⁵ , and R ¹⁶ are independently selected from the group consisting of amino, nitroso, nitro, and aminoacyl. In a preferred embodiment of the compounds of Formula Ia, the substituted lower alkyl group is substituted with one substitutent selected from the group consisting of amino, hydroxy, halo, nitroso, nitro, carboxy, acyloxy, acyl, aminoacyl, and aminocarbonyloxy. In a more preferred embodiment, the substituted lower alkyl group is substituted with one substitutent selected from the group consisting of amino, nitroso, nitro, and aminoacyl. In another aspect, this invention provides for a method for treating a viral disorder in a subject in need thereof, comprising administering a therapeutically effective amount of a compound of Formula III as defined above.

In a preferred embodiment, the viral disorder is influenza. Preferably, the viral disorder may include influenza A and influenza B. In another aspect, this invention provides pharmaceutical compositions comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of the compounds defined herein.

In yet another aspect, the present invention provides processes for preparing compounds of Formula I, Ia, II, and III.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 illustrates synthetic pathways by which diamantane may be derivatized to provide a compound according to the present invention. FIGs. 2-16 illustrate synthetic pathways by which derivatized diamantane and triamantane compounds may be prepared from diamantane and triamantane.

FIGs 17-37 are ¹ H-NMR or ¹³ C-NMR data corresponding to the Examples. FIG. 38 shows the effect of MDT-27 and MDT-44 on the growth of virus-infected Vero cells.

DETAILED DESCRIPTION OF THE INVENTION

As described above, this invention relates to diamondoid derivatives which exhibit pharmaceutical activity, useful for the treatment, inhibition, and/or prevention of viral conditions. However, prior to describing this invention in further detail, the following terms will first be defined.

Definitions

In accordance with this detailed description, the following abbreviations and definitions apply. It must be noted that as used herein, the singular forms "a", "an", and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "compounds" includes a plurality of such compounds and reference to "the dosage" includes reference to one or more dosages and equivalents thereof known to those skilled in the art, and so forth.

The publications discussed herein are provided solely for their disclosure prior to the filing date of the present application. Nothing herein is to be construed as an admission that the present invention is not entitled to antedate such publication by virtue of prior invention.

Further, the dates of publication provided may be different from the actual publication dates, which may need to be independently confirmed.

Unless otherwise stated, the following terms used in the specification and claims have the meanings given below:

"Halo" means fluoro, chloro, bromo, or iodo.

"Nitro" means the group -NO ₂ .

"Nitroso" means the group -NO.

"Hydroxy" means the group -OH.

"Carboxy" means the group -COOH.

"Lower alkyl" refers to monovalent alkyl groups having from 1 to 6 carbon atoms including straight and branched chain alkyl groups. This term is exemplified by groups such as methyl, ethyl, /so-propyl, H-propyl, H-butyl, zso-butyl, sec-butyl, t-butyl, «-pentyl and the like.

"Substituted lower alkyl" means an alkyl group with one or more substituents, preferably one to three substituents, wherein the substitutents are selected from the group consisting of amino, nitroso, nitro, halo, hydroxy, carboxy, acyloxy, acyl, aminoacyl, and aminocarbonyloxy. "Lower alkenyl" means a linear unsaturated monovalent hydrocarbon radical of two to six carbon atoms or a branched monovalent hydrocarbon radical of three to eight carbon atoms containing at least one double bond, (-C=C-). Examples of alkenyl groups include, but are not limited to, allyl, vinyl, 2-butenyl, and the like.

"Substituted lower alkenyl" means an alkenyl group with one or more substituents, preferably one to three substituents, wherein the substitutents are selected from the group consisting of amino, nitroso, nitro, halo, hydroxy, carboxy, acyloxy, acyl, aminoacyl, and aminocarbonyloxy.

The term "cycloalkyl" refers to cyclic alkyl groups of from 3 to 6 carbon atoms having a single cyclic ring including, by way of example, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. "Alkoxy" refers to the group "lower alkyl-O-" which includes, by way of example, methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, 1 ,2- dimethylbutoxy, and the like.

"Amino" refers to the group NR ^a R , wherein R ^a and R ^b are independently selected from hydrogen, lower alkyl, substituted lower alkyl, and cycloalkyl. "Acyloxy" refers to the groups H-C(O)O-, lower alkyl-C(O)O-, substituted lower alkyl-C(O)O-, lower alkenyl-C(O)O-, substituted lower alkenyl-C(O)O- and cycloalkyl- C(O)O-, wherein lower alkyl, substituted lower alkyl, lower alkenyl, substituted lower alkenyl, and cycloalkyl are as defined herein.

"Acyl" refers to the groups H-C(O)-, lower alkyl-C(O)-, substituted lower alkyl-C(O)- , lower alkenyl-C(O)-, substituted lower alkenyl-C(O)- , cycloalkyl-C(O)-, wherein lower alkyl, substituted lower alkyl, lower alkenyl, substituted lower alkenyl, and cycloalkyl are as defined herein.

"Aminoacyl" refers to the groups -NRC(O)lower alkyl, -NRC(O)substituted lower alkyl, -NRC(O)cycloalkyl, -NRC(O)lower alkenyl, and -NRC(O)substituted lower alkenyl,

wherein R is hydrogen or lower alkyl and wherein lower alkyl, substituted lower alkyl, lower alkenyl, substituted lower alkenyl, and cycloalkyl are as defined herein.

"Aminocarbonyloxy" refers to the groups -NRC(O)O-lower alkyl, -NRC(O)O- substituted lower alkyl, -NRC(O)O-lower alkenyl, -NRC(O)O-substituted lower alkenyl, - NRC(O)O-cycloalkyl, wherein R is hydrogen or lower alkyl and wherein lower alkyl, substituted lower alkyl, lower alkenyl, substituted lower alkenyl, and cycloalkyl are as defined herein.

"Pharmaceutically acceptable carrier" means a carrier that is useful in preparing a pharmaceutical composition that is generally safe, non-toxic and neither biologically nor otherwise undesirable, and includes a carrier that is acceptable for veterinary use as well as human pharmaceutical use. "A pharmaceutically acceptable carrier" as used in the specification and claims includes both one and more than one such carrier.

"Viral disorder" means any condition, disease and/or disorder related to infection by a virus. "Treating" or "treatment" of a disease includes:

(1) preventing the disease, i.e., causing the clinical symptoms of the disease not to develop in a mammal that may be exposed to or predisposed to the disease but does not yet experience or display symptoms of the disease,

(2) inhibiting the disease, i.e., arresting or reducing the development of the disease or its clinical symptoms, or

(3) relieving the disease, i.e., causing regression of the disease or its clinical symptoms.

A "therapeutically effective amount" means the amount of a compound that, when administered to a mammal for treating a disease, is sufficient to effect such treatment for the disease. The "therapeutically effective amount" will vary depending on the compound, the disease and its severity and the age, weight, etc., of the mammal to be treated.

"Pharmaceutically acceptable salt" refers to pharmaceutically acceptable salts of a compound which salts are derived from a variety of organic and inorganic counter ions well known in the art and include, by way of example only, sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium, and the like; and when the molecule contains a basic functionality, salts of organic or inorganic acids, such as hydrochloride, hydrobromide, tartrate, mesylate, acetate, maleate, oxalate and the like. Preferably, the pharmaceutically acceptable salts are of inorganic acid salts, such as hydrochloride.

"Optional" or "optionally" means that the subsequently described event or circumstance may, but need not, occur, and that the description includes instances where the event or circumstance occurs and instances in which it does not. For example, "aryl group optionally mono- or di- substituted with an alkyl group" means that the alkyl may but need not be present, and the description includes situations where the aryl group is mono- or disubstituted with an alkyl group and situations where the aryl group is not substituted with the alkyl group.

The term "mammal" refers to all mammals including humans, livestock, and companion animals.

The compounds of the present invention are generally named according to the IUPAC or CAS nomenclature system. Abbreviations which are well known to one of ordinary skill in the art may be used (e.g., "Ph" for phenyl, "Me" for methyl, "Et" for ethyl, "h" for hour or hours and "it" for room temperature).

In naming the compounds of the present invention, the numbering scheme used for the diamantane ring system (Ci ₄ H ₂₀ ) is as follows:

Positions 1, 2, 4, 6, 7, 9, 11, and 12 are bridgehead positions and the substituents at these positions are as defined for the compounds of Formula I, Ia, and II. It is to be understood that in naming the compounds based upon the above positions, the compounds may be racemic mixtures of enantiomers (e.g., the enantiomers 1 ,6-dimethyl-2-amino diamantane and 1,6- dimethyl-12-amino diamantane and the enantiomers l-methyl-7-amino diamantane and 1- methyl-11 -amino diamantane).

In naming the compounds of the present invention, the numbering scheme used for the triamantane ring system (Ci ₈ H ₂₄ ) is as follows:

Positions 1, 2, 3, 4, 6, 7, 9, 11, 12, 13, and 15 are bridgehead positions and the substituents at these positions are as defined for the compounds of Formula III.

Diamantane derivatives within the scope of this invention, including those of Formula I, Ia, and II, include those set forth in Table I as follows. The substituents at positions 1, 2, 4, 6, 7, 9, 11, and 12 are defined in the Table. The substituents at positions 3, 5, 8, 10, 13, and 14 are all hydrogen.

Table I

Diamantane derivatives within the scope of this invention, including those of Formula I, Ia, and II, also include the following:





20

wherein R is independently hydroxy, carboxy, amino, when amino preferably -NH ₂ , nitroso, nitro, or aminoacyl, when aminoacyl preferably acetamino. Preferably R is hydroxy, carboxy, amino or aminoacyl.

Specific compounds within the scope of this invention include, for example, the following compounds: 1-aminodiamantane; 4-aminodiamantane; 1,6-diaminodiamantane; 4,9-diaminodiamantane; l-methyl-2-aminodiamantane; l-methyl-4-aminodiamantane; 1- methyl-6-aminodiamantane; l-methyl-7-aminodiamantane; l-methyl-9-aminodiamantane; 1- methyl- 11-aminodiamantane; l-methyl-2,4-diaminodiamantane; l-methyl-4,6- diaminodiamantane; l-methyl-4,9-diaminodiamantane; l-amino-2-methyldiamantane; 1- amino-4-methyldiamantane; 2-amino-4-methyldiamantane; 4-methyl-9-aminodiamantane; 1 ,6-dimethyl-2-aminodiamantane; 1 ,6-dimethyl-4-aminodiamantane; 1 ,6-dimethyl- 12- aminodiamantane; l,6-dimethyl-2,4-diaminodiamantane; 1 ,6-dimethyl-2- hydroxydiamantane; l,6-dimethyl-4-hydroxydiamantane; 1 ,6-dimethyl-4- diamantanecarboxylic acid; 4,9-dimethyl-l -hydroxydiamantane; 4,9-dimethyl-l - aminodiamantane; 4,9-dimethyl-l -diamantanecarboxylic acid; 4,9-dimethyl- 1,6- diaminodiamantane; l,7-dimethyl-4-aminodiamantane; 1-acetaminodiamantane; 4- acetaminodiamantane; 1,4-diacetaminodiamantane; 1,6-diacetaminodiamantane; 1- hydroxydiamantane; 4-hydroxydiamantane; 1,6-dihydroxydiamantane; 1,7- dihydroxydiamantane; 4,9-dihydroxydiamantane; 1 -diamantanecarboxylic acid; sodium 1- diamantanecarboxylate; 4-diamantanecarboxylic acid; 1,6-diamantanedicarboxylic acid; sodium 1 ,6-diamantanedicarboxylate; 4,9-diamantanedicarboxylic acid; 1-nitrosodiamantane; 4-nitrosodiamantane; 6-bromo- 1-aminodiamantane; 1-aminomethyl-diamantane; 1-(1- aminoethyl)-diamantane; 4-aminomethyl-diamantane; 4-(l-aminoethyl)-diamantane; 1- aminomethyl-4,9-dimethyl-diamantane; 1 -(I -aminopropyl)-diamantane; 4-aminomethyl-l ,6- dimethyl-diamantane; 4-(l-aminopropyl)-diamantane; l-(l-aminoethyl)-4,9-dimethyl-

diamantane; 4-(l-aminoethyl)-l,6-dimethyl-diamantane; and pharmaceutically acceptable salts thereof. Preferred pharmaceutically acceptable salts thereof include hydrochloride salts. Triamantane derivatives within the scope of this invention include those as illustrated below. The substituents at positions 5, 8, 10, 14, 16, 17, and 18 are all hydrogen.

wherein R is independently amino, when amino preferably -NH ₂ , nitroso, nitro, or aminoacyl, when aminoacyl preferably acetamino. Specific compounds within the scope of this invention include, for example, the following compounds: 2-hydroxytriamantane; 3-hydroxytriamantane; 9-hydroxytriamantane; 9,15-dihydroxytriamantane; 2-aminotriamantane; 3-aminotriamantane; 9-aminotriamantane; 9,15-diaminotriamantane; and pharmaceutically acceptable salts thereof. Preferred pharmaceutically acceptable salts thereof include hydrochloride salts.

General Synthetic Schemes

Unsubstituted diamantane and triamantane may be synthesized by methods well known to those of skill in the art. For example, diamantane may be synthesized as described in Organic Syntheses, VoI 53, 30-34 (1973); Tetrahedron Letters, No. 44, 3877-3880 (1970); and Journal of the American Chemical Society, 87:4, 917-918 (1965). Triamantane may be synthesized as described in Journal of the American Chemical Society, 88: 16, 3862-3863 (1966).

Furthermore, unsubstituted or alkylated diamantane and triamantane can be recovered from readily available feedstocks using methods and procedures well known to those of skill in the art. For example, unsubstituted or alkylated diamantane and triamantane can be isolated from suitable feedstock compositions by methods as described in U.S. Patent No. 5,414,189, herein incorporated by reference in its entirety. Furthermore, unsubstituted or alkylated diamantane and triamantane can be isolated from suitable feedstock compositions by methods as described for higher diamondoids in U.S. Patent No. 6,861,569, herein incorporated by reference in its entirety. It will be appreciated that where typical or preferred process conditions (i.e., reaction temperatures, times, solvents, pressures, etc.) are given, other process conditions can also be used unless otherwise stated. Optimum reaction conditions may vary with feedstocks, but such conditions can be determined by one skilled in the art by routine optimization procedures. Suitable feedstocks are selected such that the feedstock comprises recoverable amounts of unsubstituted diamondoids selected from the group consisting of diamantane, triamanate, and mixtures thereof. Preferred feedstocks include, for example, natural gas condensates and refinery streams, including hydrocarbonaceous streams recoverable from cracking processes, distillations, coking, and the like. Preferred feedstocks include condensate fractions recovered from the Norphlet Formation in the Gulf of Mexico and from the LeDuc Formation in Canada.

Diamantane, isolated as described above, may be derivatized to provide a compound of Formula I, Ia, or II according to the present invention by synthetic pathways as illustrated in FIG. 1 and as described in further detail in the following examples.

Representative examples of derivatized diamantane and triamantane compounds may be prepared from diamantane and triamantane, isolated as described above, by synthetic pathways as illustrated in FIGs. 2-16, wherein D represents diamantane, triamantane, and their alkylated analogs.

The reagents used in preparing the compounds of Formula I, Ia, II, and III are either available from commercial suppliers such as Toronto Research Chemicals (North York, ON Canada), Aldrich Chemical Co. (Milwaukee, Wisconsin, USA), Bachem (Torrance, California, USA), Emka-Chemie, or Sigma (St. Louis, Missouri, USA) or are prepared by methods known to those skilled in the art following procedures set forth in references such as Fieser and Fieser's Reagents for Organic Synthesis, Volumes 1-15 (John Wiley and Sons, 1991), Rodd's Chemistry of Carbon Compounds, Volumes 1-5 and Supplementals (Elsevier Science Publishers, 1989), Organic Reactions, Volumes 1-40 (John Wiley and Sons, 1991), March's Advanced Organic Chemistry, (John Wiley and Sons, 4th Edition), and Larock's

Comprehensive Organic Transformations (VCH Publishers Inc., 1989). These schemes are merely illustrative of some methods by which the compounds of this invention can be synthesized, and various modifications to these schemes can be made and will be suggested to one skilled in the art having referred to this disclosure. As it will be apparent to those skilled in the art, conventional protecting groups may be necessary to prevent certain functional groups from undergoing undesired reactions. Suitable protecting groups for various functional groups, as well as suitable conditions for protecting and deprotecting particular function groups are well known in the art. For example, numerous protecting groups are described in T. W. Greene and G.M. Wuts, Protecting Groups in Organic Synthesis, Second Edition, Wiley, New York, 1991, and references cited therein.

The starting materials and the intermediates of the reaction may be isolated and purified if desired using conventional techniques, including but not limited to filtration, distillation, crystallization, chromatography, and the like. Such materials may be characterized using conventional means, including physical constants and spectral data.

FIG. 2 shows some representative primary derivatives of diamondoids and the corresponding reactions. As shown in FIG. 2, there are, in general, three major reactions for the derivatization of diamondoids sorted by mechanism: nucleophilic (S _N I -type) and electrophilic (S _E 2-type) substitution reactions, and free radical reaction (details for such reactions and their use with adamantane are shown, for instance in, "Recent developments in the adamantane and related polycyclic hydrocarbons" by R. C. Bingham and P. v. R. Schleyer as a chapter of the book entitled "Chemistry of Adamantanes", Springer-Verlag, Berlin Heidelberg New York, 1971 and in; "Reactions of adamantane s in electrophilic media" by I. K. Moiseev, N. V. Makarova, M. N. Zemtsova published in Russian Chemical Review, 68(12), 1001-1020 (1999); "Cage hydrocarbons" edited by George A. Olah, John Wiley & Son, Inc., New York, 1990).

S _N I reactions involve the generation of diamondoids carbocations (there are several different ways to generate the diamondoid carbocations, for instance, the carbocation is generated from a parent diamantane or triamantane, a hydroxylated diamantane or triamantane or a halogenated diamantane or triamantane, shown in FIG. 3), which subsequently react with various nucleophiles. Some representative examples are shown in FIG. 4. Such nucleophiles include, for instance, the following: water (providing hydroxylated diamantane or triamantane); halide ions (providing halogenated diamantane or triamantane); ammonia (providing aminated diamantane or triamantane); azide (providing

azidylated diamantane or triamantane); nitriles (the Ritter reaction, providing aminated diamantane or triamantane after hydrolysis); carbon monoxide (the Koch-Haaf reaction, providing carboxylated diamantane or triamantane after hydrolysis); olefins (providing alkenylated diamantane or triamantane after deprotonation); and aromatic reagents (providing arylated diamantane or triamantane after deprotonation). The reaction occurs similarly to those of open chain alkyl systems, such as /-butyl, t-cumyl and cycloalkyl systems. Since tertiary (bridgehead) carbons of diamondoids are considerably more reactive than secondary carbons under SNI reaction conditions, substitution at the tertiary carbons is favored.

Sε2-type reactions (i.e., electrophile substitution of a C-H bond via a five-coordinate carbocation intermediate) include, for instance, the following reactions: hydrogen-deuterium exchange upon treatment with deuterated superacids (e.g., DF-SbF ₅ or DSO ₃ F-SbF ₅ ); nitration upon treatment with nitronium salts, such as NO ₂ ⁺ BF ₄ ^" or NO ₂ ⁺ PF ₆ ^" in the presence of superacids (e.g., CF ₃ SO ₃ H); halogenation upon, for instance, reaction with Cl ₂ + AgSbF ₆ ; alkylation of the bridgehead carbons under the Friedel-Crafts conditions (i.e., Se2-type σ alkylation ); carboxylation under the Koch reaction conditions; and, oxygenation under S _E 2- type σ hydroxylation conditions (e.g., hydrogen peroxide or ozone using superacid catalysis involving H ₃ O ₂ ⁺ or HO ₃ ⁺ , respectively). Some representative S _E 2-type reactions are shown in FIG. 5.

Of those S _N I and S _E 2 reactions, S _N I -type reactions are the most frequently used for the derivatization of diamondoids. However, such reactions produce the derivatives mainly substituted at the tertiary carbons. Substitution at the secondary carbons of diamondoids is not easy in carbonium ion processes since secondary carbons are considerably less reactive than the bridgehead positions (tertiary carbons) in ionic processes. Free radical reactions provide a method for the preparation of a greater number of the possible isomers of a given diamondoids than might be available by ionic processes. The complex product mixtures and/or isomers which result, however, are generally difficult to separate.

FIG. 6 shows some representative pathways for the preparation of brominated diamantane or triamantane derivatives. Mono- and multi-brominated diamondoids are some of the most versatile intermediates in the derivative chemistry of diamondoids. These intermediates are used in, for example, the Koch-Haaf, the Ritter, and the Friedel-Crafts alkylation/arylation reactions. Brominated diamondoids are prepared by two different general routes. One involves direct bromination of diamantane or triamantane with elemental bromine in the presence or absence of a Lewis acid (e.g., BBr ₃ -AlBr ₃ ) catalyst. The other

involves the substitution reaction of hydroxylated diamantane or triamantane with hydrobromic acid.

Direct bromination of diamantane or triamantane is highly selective resulting in substitution at the bridgehead (tertiary) carbons. By proper choice of catalyst and conditions, one, two, three, four, or more bromines can be introduced sequentially into the molecule, all at bridgehead positions. Without a catalyst, the mono-bromo derivative is the major product with minor amounts of higher bromination products being formed. By use of suitable catalysts, however, di-, tri-, and tetra-, penta-, and higher bromide derivatives are isolated as major products in the bromination (e.g., adding catalyst mixture of boron bromide and aluminum bromide with different molar ratios into the bromine reaction mixture). Typically, tetrabromo or higher bromo derivatives are synthesized at higher temperatures in a sealed tube.

Bromination reactions of diamondoids are usually worked up by pouring the reaction mixture onto ice or ice water and adding a suitable amount of chloroform or ethyl ether or carbon tetrachloride to the ice mixture. Excess bromine is removed by distillation under vacuum and addition of solid sodium disulfide or sodium hydrogen sulfide. The organic layer is separated and the aqueous layer is extracted by chloroform or ethyl ether or carbon tetrachloride for an additional 2-3 times. The organic layers are then combined and washed with aqueous sodium hydrogen carbonate and water, and finally dried. To isolate the brominated derivatives, the solvent is removed under vacuum.

Typically, the reaction mixture is purified by subjecting it to column chromatography on either alumina or silica gel using standard elution conditions (e.g., eluting with light petroleum ether, «-hexane, or cyclohexane or their mixtures with ethyl ether). Separation by preparative gas chromatography (GC) or high performance liquid chromatography (HPLC) is used where normal column chromatography is difficult and/or the reaction is performed on extremely small quantities of material.

Similarly to bromination reactions, diamantanes and triamantanes are chlorinated or photochlorinated to provide a variety of mono-, di-, tri-, or even higher chlorinated derivatives of the diamondoids. FIG. 7 shows some representative pathways for the synthesis of chlorinated diamondoid derivatives.

FIG. 8 shows some representative pathways for the synthesis of hydroxylated diamantane or triamantane. Direct hydroxylation is also effected on diamantane or triamantane upon treatment with N-hydroxyphthalimide and a binary co-catalyst in acetic acid. Hydroxylation is a very important way of activating the diamondoid nuclei for further

derivatizations, such as the generation of diamondoid carbocations under acidic conditions, which undergo the SN I reaction to provide a variety of diamondoid derivatives. In addition, hydroxylated derivatives are very important nucleophilic agents, by which a variety of diamondoid derivatives are produced. For instance, the hydroxylated derivatives are esterified under standard conditions such as reaction with an activated acid derivative. Alkylation to prepare ethers is performed on the hydroxylated derivatives through nucleophilic substitution on appropriate alkyl halides.

The above described three core derivatives (hydroxylated diamondoids and halogenated, especially brominated and chlorinated, diamondoids), in addition to the parent diamondoids or substituted diamondoids directly separated from the feedstocks as described above, are most frequently used for further derivatizations of diamantane or triamantane, such as hydroxylated and halogenated derivatives at the tertiary carbons are very important precursors for the generation of diamondiod carbocations, which undergo the SN I reaction to provide a variety of diamondoid derivatives thanks to the tertiary nature of the bromide or chloride or alcohol and the absence of skeletal rearrangements in the subsequent reactions. Examples are given below.

FIG. 9 shows some representative pathways for the synthesis of carboxylated diamondoids, such as the Koch-Haaf reaction, starting from hydroxylated or brominated diamantane or triamantane. It should be mentioned that for most cases, using hydroxylated precursors get better yields than using brominated diamantane or triamantane. For instance, carboxylated derivatives are obtained from the reaction of hydroxylated derivatives with formic acid after hydrolysis. The carboxylated derivatives are further esterified through activation (e.g., conversion to acid chloride) and subsequent exposure to an appropriate alcohol. Those esters are reduced to provide the corresponding hydroxymethyl diamantanes or triamantanes (diamantane or triamantane substituted methyl alcohols, D-CH ₂ OH). Amide formation is also performed through activation of the carboxylated derivative and reaction with a suitable amine. Reduction of the diamondoid carboxamide with reducing agents (e.g. , lithium aluminum hydride) provides the corresponding aminomethyl diamondoids (diamantane or triamantane substituted methylamines, D-CH ₂ NH ₂ ). FIG. 10 shows some representative pathways for the synthesis of acylaminated diamondoids, such as the Ritter reaction starting from hydroxylated or brominated diamondoids. Similarly to the Koch-Haaf reaction, using hydroxylated precursors get better yields than using brominated diamondoids in most cases. Acylaminated diamondoids are converted to amino derivatives after alkaline hydrolysis. Amino diamondoids are further

converted to, without purification in most cases, amino diamondoid hydrochloride by introducing hydrochloride gas into the aminated derivatives solution. Amino diamondoids are some of very important precursors. They are also prepared from the reduction of nitrated compounds. FIG. 11 shows some representative pathways for the synthesis of nitro diamondoid derivatives. Diamondoids are nitrated by concentrated nitric acid in the presence of glacial acetic acid under high temperature and pressure. The nitrated diamondoids are reduced to provide the corresponding amino derivatives. In turn, for some cases, amino diamondoids are oxidized to the corresponding nitro derivatives if necessary. The amino derivatives are also synthesized from the brominated derivatives by heating them in the presence of formamide and subsequently hydrolyzing the resultant amide.

Similarly to the hydroxylated compounds, amino diamondoids are acylated or alkylated. For instance, reaction of an amino diamondoid with an activated acid derivative produces the corresponding amide. Alkylation is typically performed by reacting the amine with a suitable carbonyl containing compound in the presence of a reducing agent (e.g., lithium aluminum hydride). The amino diamondoids undergo condensation reactions with carbamates such as appropriately substituted ethyl N-arylsulfonylcarbamates in hot toluene to provide, for instance, TV-arylsulfonyl-N'- diamondoidylureas.

FIG. 12 presents some representative pathways for the synthesis of alkylated, alkenylated, alkynylated and arylated diamondoids, such as the Friedel-Crafts reaction. Ethenylated diamondoid derivatives are synthesized by reacting a brominated diamondoid with ethylene in the presence OfAlBr ₃ followed by dehydrogen bromide with potassium hydroxide (or the like). The ethenylated compound is transformed into the corresponding epoxide under standard reaction conditions (e.g., 3-chloroperbenzoic acid). Oxidative cleavage (e.g., ozonolysis) of the ethenylated diamondoid affords the related aldehyde. The ethynylated diamondoid derivatives are obtained by treating a brominated diamondoid with vinyl bromide in the presence Of AlBr ₃ . The resultant product is dehydrogen bromide using KOH or potassium t-butoxide to provide the desired compound.

More reactions are illustrative of methods which can be used to functionalize diamondoids. For instance, fluorination of a diamondoid is carried out by reacting the diamondoid with a mixture of poly(hydrogen fluoride) and pyridine (30% Py, 70% HF) in the presence of nitronium tetrafluoroborate. Sulfur tetrafluoride reacts with a diamondoid in the presence of sulfur monochloride to afford a mixture of mono-, di-, tri- and even higher fluorinated diamondoids. Iodo diamondoids are obtained by a substitutive iodination of chloro, bromo or hydroxyl diamondoids.

Reaction of the brominated derivatives with hydrochloric acid in dimethylformamide (DMF) converts the compounds to the corresponding hydroxylated derivatives. Brominated or iodinated diamondoids are converted to thiolated diamondoids by way of, for instance, reacting with thioacetic acid to form diamondoid thioacetates followed by removal of the acetate group under basic conditions. Brominated diamondoids, e.g., D-Br, are heated under reflux with an excess (10 fold) of hydroxyalkylamine, e.g., HO-CH ₂ CH ₂ -NH ₂ , in the presence of a base, e.g., triethylamine, diamondoidyloxyalkylamine, e.g., D-O-CH ₂ CH ₂ -NH ₂ , is obtained. On acetylation of the amines with acetic anhydride and pyridine, a variety of N- acetyl derivatives are obtained. Direct substitution reaction of brominated diamondoids, e.g., D-Br, with sodium azide in dipolar aprotic solvents, e.g., DMF, to afford the azido diamondoids, e.g., D-N ₃ .

Diamondoid carboxylic acid hydrazides are prepared by conversion of diamondoid carboxylic acid into a chloroanhydride by thionyl chloride and condensation with isonicotinic or nicotinic acid hydrazide (FIG. 13). Diamondoidones or "diamondoid oxides" are synthesized by photooxidation of diamondoids in the presence of peracetic acid followed by treatment with a mixture of chromic acid-sulfuric acid. Diamondoidones are reduced by, for instance, LiAlH ₄ , to diamondoidols hydroxylated at the secondary carbons. Diamondoidones also undergo acid- catalyzed (HCl-catalyzed) condensation reaction with, for example, excess phenol or aniline in the presence of hydrogen chloride to form 2,2-bis(4-hydroxyphenyl) diamondoids or 2,2- bis(4-aminophenyl) diamondoids.

Diamondoidones (e.g., D=O) are treated with RCN (R = hydrogen, alkyl, aryl, etc.) and reduced with LiAlH ₄ to give the corresponding C-2-aminomethyl-C-2-D-OH, which are heated with COCl ₂ or CSCl ₂ in toluene to afford the following derivatives shown in formula IV (where Z = O or S):

IV

Diamondoidones react with a suitable primary amine in an appropriate solvent to form the corresponding imines. Hydrogenation of the imines in ethanol using PdVC as the catalyst at about 50 ⁰ C to afford the corresponding secondary amines. Methylation of the secondary amines following general procedures (see, for instance, H. W. Geluk and V. G. Keiser,