KR100628586B1 - 3-desoxy-vitamin d3 analog esters - Google Patents

Abstract

The present invention relates to formula (I) or salts thereof. The present invention also relates to the use of a compound of formula (I) or a salt thereof as a medicament:

Formula I

Where

Dotted lines, R ¹ , R ² , R ³ , R ⁴ and L are as defined in the claims.

Description

3-desoxy-vitamin di3 analogous ester {3-DESOXY-VITAMIN D3 ANALOG ESTERS}             

The present invention relates to methods of treating a variety of diseases using vitamin D ₃ analogs and methods of making the analogs. Specifically, the present invention relates to 3-desoxy-20-desmethyl-20-cyclopropyl vitamin D ₃ analogous esters and methods of making and using the same.

Osteoporosis is the most common form of metabolic bone disease and can be considered a fracture that is a precursor to bone loss (osteopathy). Osteoporosis may occur secondary to many underlying diseases, but 90% of all cases appear idiopathic. Postmenopausal women are at risk of idiopathic osteoporosis (postmenopausal or type I osteoporosis), and the elderly of men or women are another group at very high risk of idiopathic osteoporosis (old age or type II osteoporosis). Osteoporosis is also associated with corticosteroid therapy, immobilized or prolonged bed rest, alcoholism, diabetes, gonadotoxic chemotherapy, hyperprolactinosis, anorexia, anorexia nervosa, primary and secondary amenorrhea, transplant immunosuppression and ovarian resection have. Postmenopausal osteoporosis is characterized by vertebral fractures, and femoral neck fractures are the main features of old age osteoporosis.

The mechanism of osteoporotic bone loss is believed to be associated with an imbalance in skeletal reproduction. This process is defined as bone remodeling and occurs in a series of distinct active pockets. These pockets appear spontaneously in the bone matrix on the bone surface given as a bone resorption site. Osteoclasts (bone lysis or reuptake cells) are generally responsible for resorption of bone portions of certain dimensions. After this resorption process, osteoblasts (osteoblasts) appear and then the space left by the osteoclasts is filled with new bone.

In healthy adults, osteoclasts and osteoblasts function to balance bone formation and bone resorption. However, in osteoporosis, the imbalance of the bone remodeling process progresses, so that the bone replacement rate is slower than the bone loss rate. This imbalance occurs to some extent in most individuals as they age, but is much more severe and younger in postmenopausal osteoporosis, in postmenopausal surgery, or in a personified situation, such as due to an immunosuppressive condition such as corticosteroid therapy or organ transplantation. It can also occur with age.

In order to increase bone mass in humans with osteoporosis, various methods have been proposed, including the administration of androgens, fluoride salts and parathyroid hormones and modified parathyroid hormones. It has also been proposed that bisphosphonates, calcitonin, calcium, 1,25-dihydroxy vitamin D ₃ and some analogs thereof, and / or estrogens, alone or in combination, are useful for preserving existing bone mass.

Vitamin D ₃ is an important factor in calcium metabolism by promoting long-term absorption of calcium and phosphorus, maintaining sufficient calcium and phosphorus serum concentrations, and increasing the movement of calcium into and out of the bone. Vitamin D ₃ is hydroxylated in vivo, and the resulting 1-α, 25-dihydroxy metabolite is the active substance. Bone assimilation activity has been proposed in animal experiments with 1,25- (OH) ₂ vitamin D ₃ . Aerssens et al., Calcif Tissue Int, 55: 443-450 (1994) report the effect of 1α-hydroxy vitamin D ₃ on bone strength and composition in rats growing with or without corticosteroid treatment. However, use in humans is limited to preventing resorption due to poor therapeutic rates (hypercalciuria, hypercalcemia and nephrotoxicity).

Dechant and Goa, "Calcitriol. A review of its use in the treatment of postmenopausal osteoporosis and its potential in corticosteroid-induced osteoporosis", Drugs Aging, NEW ZEALAND 5 (4): 300-17 (1994), 1, Clinical trials of 622 women with postmenopausal osteoporosis reported that 25-dihydroxyvitamin D ₃ (calcitriol) is effective in the treatment of postmenopausal osteoporosis (also promising for corticosteroid-induced osteoporosis). have. If calcitriol (0.25 μg twice daily) was given to patients with mild or moderate symptoms (but not more severe patients) after three years of treatment compared to patients receiving 1000 mg / day of elemental calcium The new spinal fracture rate was three times lower. In patients beginning long-term treatment with prednisone or prednisolone, steroid-induced bone loss was prevented when calcitriol 0.5-1.0 μg / day and 1000 mg / day calcium were administered with or without intranasal or 400 calItonin 400 IU / day. Above all, calcitriol is well tolerated. In the recommended dosages, hypercalcemia generally occurs rarely and weakly in response to a decrease in calcium absorption and / or calcitriol dosage. However, due to the narrow therapeutic range of calcitriol, it is necessary to properly monitor and monitor the serum calcium and creatinine concentrations in use. This study clearly identifies the major limitations of calcitriol therapy as an approximation of the therapeutic and toxic amounts.

In a particular 3-desok -20- cyclopropyl-vitamin D ₃ analogs are disclosed to inhibit the in vitro cell differentiation in prostate cancer cells [( "20-cyclopropyl-cholecalciferol vitamin D ₃ analogues (20-Cyclopropyl- cholecalciferol Vitamin D ₃ Analogs) ", M. Koike et al., Anticancer Research, 19: 1689-1698 (1999).

Parathyroidism

Secondary hyperparathyroidism is commonly found in patients with chronic renal failure. It has been established that a decrease in 1,25 (OH) ₂ vitamin D ₃ (calcitriol) synthesis in the kidney is one of the major mechanisms leading to secondary hyperparathyroidism in these patients, and that calcitriol has a direct inhibitory effect on PTH synthesis Presented. Therefore, administration of calcitriol has been recommended for the treatment of secondary hyperparathyroidism in such patients. However, as noted above, calcitriol has the potential hypercalcemia effect, showing a narrow therapeutic range that limits its use, mainly at high doses. Thus, there is a need for an alternative means of treating parathyroidism without causing such unwanted hypercalcemia effects.

Although various compounds can be used to treat these and other diseases, many compounds have unwanted side effects and / or relatively unstable, i.e., short shelf life. Thus, there is a continuing need for other compounds useful in the treatment of these diseases.

One aspect of the present invention provides a 3-deoxy vitamin D ₃ analogous ester of formula (I) or a salt thereof and methods of using and preparing the same:

Where

The dotted line optionally represents a double bond;

L is -CH ₂ -CH ₂ -CH _2- , -CH ₂ -CH = CH-, -CH ₂ -C≡C-, -CH ₂ -CH ₂ -C (= O)-, and -CH = CH -CH = CH- is a linking group selected from the group consisting of;

R ² and R ³ are each independently alkyl or haloalkyl, or R ² and R ³ together with the carbon atom to which they are attached form cycloalkyl;

R ¹ and R ⁴ are each independently hydrogen, alkyl, acyl or other hydroxy protecting group;

Provided that at least one of R ¹ and R ⁴ is an acyl group.

"Acetate" or "Ac" is used interchangeably herein and refers to a residue of the formula -C (= 0) CH ₃ .

"Acyl" refers to a moiety of the formula -C (O) R 'wherein R' is alkyl, heteroalkyl, cycloalkyl, aryl, heteroaryl, aralkyl or heteroaralkyl.

"Alkyl" means a linear fully saturated hydrocarbon residue having 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms or a branched fully saturated hydrocarbon residue having 3 or 6 carbon atoms.

"Aralkyl" means a moiety of the formula -R ^a -R ^b , wherein R ^a is alkyl and R ^b is aryl.

"Aryl" refers to a monocyclic or bicyclic aromatic hydrocarbon residue. In addition, one or more, preferably one, two or three hydrogen atoms of the aryl moiety may be substituted with halo, nitro, cyano, hydroxy, amino, alkyl or alkoxy. Examples of aryl groups include phenyl and naphthalenyl, which may be substituted with one or more substituents mentioned above. Preferably, aryl is phenyl.

"Cycloalkyl" means a fully saturated cyclic hydrocarbon moiety of a ring having 3 to 6 carbon atoms, such as cyclopropyl, cyclopentyl, and the like.

"Ester" refers to a compound comprising a moiety of the formula -OC (= 0) -R 'wherein R' is alkyl, heteroalkyl, cycloalkyl, aryl, heteroaryl, aralkyl or heteroaralkyl. .

"Haloalkyl" means an alkyl moiety as defined above wherein one or more hydrogen atoms bonded to the carbon skeleton are replaced by one or more halides. Preferably, the halide is fluoride.

“Heteroalkyl” is one or more, preferably one, two or selected from —NR ^a R ^b and —OR ^c , wherein R ^a , R ^b and R ^c are independently of each other hydrogen, alkyl or a corresponding protecting group It means an alkyl moiety as defined above having three substituents.

"Heteroaralkyl" means a moiety of the formula -R ^a -R ^b , wherein R ^a is alkyl and R ^b is heteroaryl.

"Heteroaryl" means a monocyclic or bicyclic radical having 5 to 12 ring atoms containing one, two or three ring heteroatoms selected from N, O and S and having at least one aromatic ring with the remaining ring atoms C; Where the point of attachment of the heteroaryl radical is present on the aromatic ring. In addition, one or more, preferably one, two or three hydrogen atoms of the heteroaryl moiety may be substituted with the substituents mentioned above for the aryl group.

The terms “hydroxy protecting group” and “other hydroxy protecting group” are used interchangeably herein and refer to hydroxy protecting groups known to those skilled in the art, except for the alkyl or acyl groups specifically referred to herein. Representative hydroxy protecting groups include silyl ethers, carbonates, carbamates, substituted methyl ethers, substituted ethyl ethers, and the like. A list of other suitable hydroxy protecting groups can be found, for example, in Protective groups in Organic Chemistry , 3rd edition, TW Green and PGM Wuts, John Wiley & Sons, New York, 1999, which is incorporated herein by reference in its entirety. It is incorporated.

"Pharmaceutically acceptable excipient" means an excipient that is useful for the manufacture of a pharmaceutical composition, which is generally safe, nontoxic, and biologically or otherwise unnecessary, and includes excipients that can be used not only as human pharmaceuticals but also as veterinary. . As used herein, “pharmaceutically acceptable excipient” is one that includes one or more such excipients.

A "therapeutically effective amount" means an amount of a compound that is sufficient to treat or prevent a disease when administered to a mammal to treat or prevent the disease. A "therapeutically effective amount" depends on the severity of the compound, disease and condition, the age, weight, etc. of the patient being treated.

"Treatment" of a disease involves (1) preventing the disease, i.e. preventing the development of clinical symptoms of the disease in mammals that are exposed to or susceptible to disease but have not yet experienced or exhibited disease symptoms, (2) Inhibiting the disease, i.e. stopping or reducing the progression of the disease or its clinical symptoms, and (3) alleviating the disease, i.e. alleviating the disease or its clinical symptoms.

When referring to a chemical reaction, the terms “treatment”, “contacting” and “reaction” are used interchangeably herein, and the addition and mixing of two or more reagents under appropriate conditions to produce the indicated and / or desired product. Refer. It is recognized that the reaction to produce the indication and / or the desired product does not necessarily need to be generated directly from the combination of the two reagents initially added. That is, there may be one or more intermediates prepared from a mixture that ultimately form the indication and / or the desired product.

As used herein, the terms “defined above” and “as defined herein” are incorporated by reference to the broad, as well as preferred, more preferred and most preferred definitions when referring to variables.

"Haloalkyl" refers to an alkyl radical as defined above wherein one or more hydrogen atoms bonded to the carbon backbone are replaced with one or more halides. Preferred halides are fluorides.

"Prodrug" means any compound that, when administered to a mammalian subject, releases the active parent drug of Formula (I) in vivo. Prodrugs of compounds of formula (I) are prepared by modifying functional groups present in the compounds of formula (I) in such a way that they can be cleaved in vivo to release the parent compound. Prodrugs include compounds of formula (I) wherein the hydroxyl group of formula (I) is bonded to any group that can be cleaved in vivo to regenerate free hydroxy groups. Examples of prodrugs include esters (such as acetates, formate, and benzoate derivatives), carbamates (such as N, N-dimethylaminocarbonyl), and ethers of hydroxy functional groups of the compounds of formula (I), and the like. , But not limited to these. Such compounds are commonly prepared by those skilled in the art by acylating or etherifying the hydroxyl groups in the parent molecule.

"Hydroxy protecting group" refers to an atomic group that reduces or interferes with the reactivity of the hydroxy group when the hydroxy group of the molecular mask is bonded. Examples of such protecting groups are described in TW Green and PGM Futs, Protective groups in Organic Chemistry, (Wiley, 2 ^nd ed. 1999) and Harrison and Harrison et al., Compendium of Synthetic Organic Methods, Vols. 1-8 (John Wiley and Sons, 1971-1996). Representative hydroxy protecting groups include those in which the hydroxy group is acylated or alkylated, such as benzyl, trityl ether, alkyl ether, tetrahydropyranyl ether, trialkylsilyl ether and allyl ether.

Surprisingly, certain 3-desoxy-1-alpha-hydroxy-20-cyclopropyl cholecalciferol vitamin D ₃ compounds, which until now have only known antiproliferative activity, have 1,25-dihydroxy in increasing bone formation. it was found that significantly more efficient than vitamin D _3.

Thus, one aspect of the present invention relates to administering to a patient a 3-desoxy-1-alpha-hydroxy vitamin D ₃ analog of Formula I or a prodrug or salt thereof, preferably a compound of Formula I or a salt thereof Provided are methods of treating osteoporosis or hyperparathyroidism, including:

Formula I

Where
The dotted line optionally represents a double bond;

L is -CH ₂ -CH ₂ -CH _2- , -CH ₂ -CH = CH-, -CH ₂ -C≡C-, -CH ₂ -CH ₂ -C (= O)-, and -CH = CH -CH = CH- is a linking group selected from the group consisting of;

R ¹ and R ⁴ are each independently selected from the group consisting of hydrogen and alkyl;

R ² and R ³ are each independently selected from the group consisting of alkyl and haloalkyl, or R ² and R ³ together with the carbon atom to which they are attached form cycloalkyl.

Another aspect of the present invention provides a process for preparing a compound of formula I, comprising contacting a ketone of formula II with a phosphine oxide compound of formula III under conditions sufficient to produce a compound of formula I: :

Formula I

Where

Ar ¹ and Ar ² are each independently optionally substituted aryl;

The dotted line optionally represents a double bond;

L is -CH ₂ -CH ₂ -CH _2- , -CH ₂ -CH = CH-, -CH ₂ -C≡C-, -CH ₂ -CH ₂ -C (= O)-, and -CH = CH -CH = CH- is a linking group selected from the group consisting of;

R ¹ and R ⁴ are each independently selected from the group consisting of hydrogen, alkyl and hydroxy protecting groups;

R ² and R ³ are each independently selected from the group consisting of alkyl and haloalkyl, or R ² and R ³ together with the carbon atom to which they are attached form cycloalkyl.

In one embodiment of the process for preparing the compound of formula I, R ⁴ is hydrogen. In a practical embodiment, the method comprises the steps of protecting the hydroxy group of the ketone of formula II and contacting the ketone of formula II with the phosphine oxide compound of formula III prior to the step of contacting with the phosphine oxide compound of formula III It further comprises the step of removing the hydroxy protecting group after preparing the compound of.

Preferred are compounds of formula (I) or salts thereof, preferably compounds of formula (I):

Formula I

Where

The dotted line optionally represents a double bond;

L is -CH ₂ -CH ₂ -CH _2- , -CH ₂ -CH = CH-, -CH ₂ -C≡C-, -CH ₂ -CH ₂ -C (= O)-, and -CH = CH -CH = CH- is a linking group selected from the group consisting of;

R ² and R ³ are each independently alkyl or haloalkyl, or R ² and R ³ together with the carbon atom to which they are attached form cycloalkyl;

R ¹ and R ⁴ are each independently hydrogen, alkyl, acyl or other hydroxy protecting group;

Provided that at least one of R ¹ and R ⁴ is an acyl group.

More preferred are compounds of formula (IB):

Where

R ¹ , R ² , R ³ , R ⁴ and L are as defined in claim 1.

Another preferred embodiment of the invention is a compound of formula

Formula I

Where

L is selected from the group consisting of —CH ₂ —CH ₂ —CH ₂ —, —CH ₂ —CH═CH—, —CH ₂ —C≡C—, and —CH═CH—CH═CH—.

Still more preferred are wherein L is a compound of the -CH ₂ -CH = CH- and the formula (I) selected from the group consisting of a connecting group -CH ₂ -C≡C-.

Also preferred are compounds of formula I, wherein R ¹ is an acyl group.

Another preferred of the present invention is a compound of formula I, wherein R ⁴ is an acyl group.

Also preferred are compounds of formula I, wherein R ² and R ³ are each independently selected from the group consisting of alkyl and haloalkyl.

Another preferred embodiment of the invention is a compound of formula I, wherein R ² and R ³ are trifluoromethyl.

Especially preferred

[1R- (1α (E), 3aβ, 7aα)] octahydro-7a-methyl-1- [5,5,5-trifluoro-4-hydroxy-4- (trifluoromethyl) -2- Pentynyl] cyclopropyl] -4H-inden-4-ol;

[1R- (1α (E), 3aβ, 7aα)] octahydro-7a-methyl-1- [1- [1- [5,5,5-trifluoro-4-hydroxy-4- (trifluoro Rhomethyl) -2-pentynyl] cyclopropyl] -4H-inden-4-one;

[1R- (1α (E), 3aβ, 7aα)] octahydro-7a-methyl-1- [1- [5,5,5-trifluoro-4-trifluoromethyl) -4-[(trimethyl Silyl) oxy] -2-pentynyl] cyclopropyl] -4H-inden-4-one;

3-decoxy-1,25-dihydroxy-20-methyl-23- (E) -ene-26,27-hexafluoro-21,28-cyclocholecalciferol;

3-decoxy-1,25-dihydroxy-20-methyl-23- (Z) -ene-26,27-hexafluoro-21,28-cyclocholecalciferol;

3-decoxy-1,25-dihydroxy-20-methyl-23-yne-21,28-cyclocholecalciferol;

3-decoxy-1,25-dihydroxy-20-methyl-23-yne-26,27-hexafluoro-21,28-cyclocholecalciferol;

3-decoxy-1,25-dihydroxy-20-methyl-21,28-cyclocholecalciferol;

3-decoxy-1 α-acetoxy-25-hydroxy-20-cyclopropyl-23E-ene-26,27-hexafluorocholecalciferol; And

Compound of formula (I) selected from the group consisting of 3-decyl-lα, 25-diacetoxy-20-cyclopropyl-23E-ene-26,27-hexafluorocholecalciferol.

Even more desirable

(a) contacting a ketone of formula II with a phosphine oxide compound of formula III under conditions sufficient to prepare a compound of formula I; And

(b) comprising the step of acylating topically acylating a compound of formula (I) under conditions sufficient to R ¹ and R ⁴ is prepared a compound of R ¹ and R due formula I know one or more of the ^4, when all is not an acyl group Is a process for preparing a compound of formula (I):

Formula II

Formula III

Where

Ar ¹ and Ar ² are each independently optionally substituted aryl;

The dotted line optionally represents a double bond;

L is -CH ₂ -CH ₂ -CH _2- , -CH ₂ -CH = CH-, -CH ₂ -C≡C-, -CH ₂ -CH ₂ -C (= O)-, and -CH = CH -CH = CH- is a linking group selected from the group consisting of;

R ² and R ³ are each independently alkyl or haloalkyl, or R ² and R ³ together with the carbon atom to which they are attached form cycloalkyl;

R ¹ and R ⁴ are each independently alkyl, acyl or hydroxy protecting groups.

Especially preferred are the above processes wherein R ¹ and R ⁴ are hydroxy protecting groups.

Also particularly preferred is a hydroxy protecting group under conditions sufficient for the acylation step (b) to produce (i) the resulting compound of step (a) with a 1-hydroxy-3-decoxy vitamin D ₃ analog of formula (Ia) Removing the hydroxy group by contact with the removal compound, and

(ii) contacting said 1-hydroxy-3-decoxy vitamin D ₃ analog with an acylating agent under conditions sufficient to produce a 3-deoxy vitamin D ₃ analogous ester of formula (Ic) :

Where

R ^1a is an acyl group;

R ^4a is hydrogen or an acyl group.

Also particularly preferred is the above process wherein R ^4a is an acyl group.

More preferred is the above process wherein Ar ¹ and Ar ² are phenyl.

Another preferred embodiment of the invention is a compound of formula (I) prepared according to the above process.

Also preferred are pharmaceutical compositions comprising a compound of formula (I) and a pharmaceutically acceptable excipient.

Even more preferred are the compounds of formula (I) for use as therapeutically active substances.

Another preferred embodiment of the invention is a compound of formula (I) for the manufacture of a medicament for the prevention and treatment of bone related diseases.

Also preferred is a method of treating a bone related disease comprising administering a compound of formula (I) to a patient.

Even more preferred is the above treatment method wherein the disease is selected from parathyroid hyperplasia, secondary parathyroid hyperplasia, renal dysplasia and osteoporosis.

Another preferred embodiment of the invention comprises administering to a patient a compound of formula (I) or a prodrug or salt thereof, preferably a compound of formula (I) or a salt thereof, most preferably a compound of formula (I) Treatment of related diseases is:

Formula I

Where

The dotted line optionally represents a double bond;

L is -CH ₂ -CH ₂ -CH _2- , -CH ₂ -CH = CH-, -CH ₂ -C≡C-, -CH ₂ -CH ₂ -C (= O)-, and -CH = CH -CH = CH- is a linking group selected from the group consisting of;

R ¹ and R ⁴ are each independently selected from the group consisting of hydrogen and alkyl;

R ² and R ³ are each independently selected from the group consisting of alkyl and haloalkyl, or R ² and R ³ together with the carbon atom to which they are attached form cycloalkyl.

Especially preferred are such methods for treating bone related diseases comprising administering a compound of formula (I) to a patient.

Also preferred is the use of a compound of formula (I) or a prodrug or salt thereof, preferably a compound of formula (I) or a salt thereof, most preferably a compound of formula (I) for the treatment and prophylaxis of bone related diseases to be:

Formula I

Where

The dotted line optionally represents a double bond;

L is -CH ₂ -CH ₂ -CH _2- , -CH ₂ -CH = CH-, -CH ₂ -C≡C-, -CH ₂ -CH ₂ -C (= O)-, and -CH = CH -CH = CH- is a linking group selected from the group consisting of;

R ¹ and R ⁴ are each independently selected from the group consisting of hydrogen and alkyl;

R ² and R ³ are each independently selected from the group consisting of alkyl and haloalkyl, or R ² and R ³ together with the carbon atom to which they are attached form cycloalkyl.

Particularly preferred is the above use, wherein the bone-related disease is parathyroidism, renal dysplasia or osteoporosis.

Preference is given to the above method or use wherein the compound is represented by the formula

Formula IB

Where

R ¹ , R ² , R ³ , R ⁴ and L are as defined above.

Even more preferred is a link wherein L is selected from the group consisting of -CH ₂ -CH ₂ -CH _2- , -CH ₂ -CH = CH-, -CH ₂ -C≡C-, and -CH = CH-CH = CH-. The above method or use.

Also preferred is the above method or use, wherein L is a linking group selected from the group consisting of -CH ₂ -CH = CH- and -CH ₂ -C≡C-.

Even more preferred is the above method or use, wherein R ¹ is hydrogen.

Also preferred is the above method or use, wherein R ¹ and R ⁴ are hydrogen.

Especially preferred are the above methods or uses, wherein R ² and R ³ are each independently selected from the group consisting of alkyl and haloalkyl.

Even more particularly preferred is the above method or use, wherein R ² and R ³ are both trifluoromethyl.

In addition, particularly preferred are such methods or uses, wherein the disease is osteoporosis.

Also preferred is the above method or use, wherein the disease corrects or reduces the occurrence of fractures.

Even more particularly preferred is the above method or use wherein the patient is at an increased risk of fracture due to a decrease in the amount of estrogen.

Also preferred is the above method or use, wherein the patient is female.

Even more preferred is the above method or use, wherein the bone mineral density of the patient is increased.

Also particularly preferred are the above methods or uses wherein the patient is also treated with bisphosphonates, estrogens, selective estrogen receptor modulators or assimilation agents.

Even more preferred is a process for preparing a compound of formula I comprising contacting a ketone of formula II with a phosphine oxide compound of formula III under conditions sufficient to prepare a compound of formula I:

Formula I

Formula II

Formula III

Where

Ar ¹ and Ar ² are each independently optionally substituted aryl;

The dotted line optionally represents a double bond;

L is -CH ₂ -CH ₂ -CH _2- , -CH ₂ -CH = CH-, -CH ₂ -C≡C-, -CH ₂ -CH ₂ -C (= O)-, and -CH = CH -CH = CH- is a linking group selected from the group consisting of;

R ¹ and R ⁴ are each independently selected from the group consisting of hydrogen and alkyl;

R ² and R ³ are each independently selected from the group consisting of alkyl and haloalkyl, or R ² and R ³ together with the carbon atom to which they are attached form cycloalkyl.

Especially preferred is the above process wherein R ⁴ is hydrogen.

Furthermore, particularly preferred are the steps of protecting the hydroxy group of the ketone of formula II and contacting the ketone of formula II with the phosphine oxide compound of formula III prior to the step of contacting with the phosphine oxide compound of formula III And then removing the hydroxy protecting group.

One aspect of the present invention provides 3-desoxy-20-desmethyl-20-cyclopropyl vitamin D ₃ analogous ester of formula I or a salt thereof:

Formula I

Where

The dotted line optionally represents a double bond;

L is -CH ₂ -CH ₂ -CH _2- , -CH ₂ -CH = CH-, -CH ₂ -C≡C-, -CH ₂ -CH ₂ -C (= O)-, and -CH = CH -CH = CH- is a linking group selected from the group consisting of;

R ² and R ³ are each independently alkyl or haloalkyl, or R ² and R ³ together with the carbon atom to which they are attached form cycloalkyl;

R ¹ and R ⁴ are each independently hydrogen, alkyl, acyl or other hydroxy protecting group;

Provided that at least one of R ¹ and R ⁴ is an acyl group.

Surprisingly, it has been found that compounds of formula (I) wherein at least one of R ¹ and R ⁴ are acyl groups are unexpectedly stable and crystalline compared to compounds in which both R ¹ and R ⁴ are hydrogen, ie the parent diol.

When the cyclopentane ring moiety of formula (I) does not contain a double bond, ie no dashed line, the stereochemistry of the side chain of the cyclopentane ring system may be alpha or beta. Preferably, the stereochemistry of the side chains of the cyclopentane ring system is beta, as represented by Formula Id:

In one particular embodiment of the invention, the 3-deoxy vitamin D ₃ analogous ester is represented by the formula (IB):

Formula IB

Where

R ¹ , R ² , R ³ , R ⁴ and L are as defined above.

In another embodiment, the linking group L consists of —CH ₂ —CH ₂ —CH ₂ —, —CH ₂ —CH═CH—, —CH ₂ —C≡C—, and —CH═CH—CH═CH— Selected from the group. Preferably, L is -CH ₂ -CH = CH- or -CH ₂ -C≡C-. More preferably, L is -CH ₂ -CH = CH- wherein the double bond is present as a trans.

In one embodiment, R ¹ is preferably an acyl group, more preferably acetyl.

In another embodiment, R ¹ is an acyl group and R ⁴ is hydrogen or an acyl group.

In another embodiment, R ¹ is an acyl group and R ² and R ³ are each independently selected from the group consisting of methyl, ethyl and trifluoromethyl.

In another embodiment, R ² and R ³ are alkyl or haloalkyl, preferably methyl or trifluoromethyl, most preferably trifluoromethyl.

Numerous different preferred substituents have been presented above and subsequent preferred substituents represent compounds of the invention that are more preferred than those which are not followed by particularly preferred substituents. However, these preferred substituents are generally independent, although some of them are mutually exclusive, and one or more substituents following them represent more preferred compounds than followed by fewer substituents.

Selected Compounds of the Invention

In a preferred embodiment, the present invention relates to a method of treating osteoporosis, parathyroidism or autoimmune disease by administering to a patient a ₃ -deoxy vitamin D ₃ analog of Formula I:

Formula I

Where

R ¹ , R ² , R ³ , R ⁴ and L are as defined in the Summary of the Invention.

When the cyclopentane ring moiety of formula (I) does not contain a double bond, ie when no dashed line is present, the stereochemistry of the side chain of the cyclopentane ring system is beta, as represented by formula (Id):

Chemical Formula Id

In one embodiment, the 3-deoxy vitamin D ₃ analog is represented by Formula IB:

Formula IB

Where

R ¹ , R ² , R ³ , R ⁴ and L are as defined in the Summary of the Invention.

In another embodiment, the linking group L consists of -CH ₂ -CH ₂ -CH _2- , -CH ₂ -CH = CH-, -CH ₂ -C≡C-, and -CH = CH-CH = CH- Selected from the group. Preferably, L is -CH ₂ -CH = CH- or -CH ₂ -C≡C-. More preferably, L is -CH ₂ -CH = CH-, wherein the double bond is present as a trans.

In another embodiment preferably R ¹ is hydrogen.

In another embodiment preferably R ⁴ is hydrogen.

In another embodiment both R ¹ and R ⁴ are hydrogen.

In another specific embodiment R ² and R ³ are each independently alkyl or haloalkyl, preferably methyl or trifluoromethyl.

Numerous different preferred substituents have been presented above and subsequent preferred substituents represent compounds of the invention that are more preferred than those which are not followed by particularly preferred substituents. However, these preferred substituents are generally independent, although some of them are mutually exclusive, and one or more substituents following them represent more preferred compounds than followed by fewer substituents.

Common synthesis

Although a number of synthetic methods are available for the preparation of compounds of formula (I), one particular embodiment for preparing compounds of formula (I) involves coupling ketones with phosphine oxides. Specifically, the compound of formula (I) comprises (a) contacting a compound of formula (II) with a phosphine oxide compound of formula (III) under conditions sufficient to prepare a compound of formula (I), and (b) R ¹ and R ⁴ Can be prepared by acylating a compound of formula (I) with an acylating agent under conditions sufficient to produce a compound of formula (I) wherein at least one of R ¹ and R ⁴ is an acyl group when both are not acyl groups:

Formula II

Formula III

Where

Ar ¹ and Ar ² are each independently optionally substituted aryl;

The dotted line optionally represents a double bond;

L is -CH ₂ -CH ₂ -CH _2- , -CH ₂ -CH = CH-, -CH ₂ -C≡C-, -CH ₂ -CH ₂ -C (= O)-, and -CH = CH -CH = CH- is a linking group selected from the group consisting of;

R ² and R ³ are each independently alkyl or haloalkyl, or R ² and R ³ together with the carbon atom to which they are attached form cycloalkyl;

R ¹ and R ⁴ are each independently hydrogen, alkyl, acyl or hydroxy protecting groups.

In one embodiment R ¹ and R ⁴ are hydroxy protecting groups. In this particular embodiment, the acylation step (b) comprises (i) removing the hydroxy protecting group under conditions sufficient to produce the compound of step (a) under the preparation of the 1-hydroxy-3-decoxy vitamin D ₃ analog of Formula (Ia) Removing the hydroxy group by contacting the compound, and (ii) the 1-hydroxy-3-deoxy vitamin D ₃ analogue under conditions sufficient to produce a ₃ -deoxy vitamin D ₃ analogous ester of formula (Ic) Contacting with an acylating agent includes:

Formula Ia

Formula Ic

Where

R ^1a is an acyl group;

R ^4a is hydrogen or an acyl group.

In another embodiment, R ^4a is an acyl group.

In another embodiment, Ar ¹ and Ar ² are phenyl.

Suitable hydroxy protecting groups are known to those skilled in the art, and examples of such hydroxy protecting groups are described in Protective groups in Organic Synthesis , 3rd edition, TW Green and PGM Wuts, John Wiley & Sons, New York, 1999 and Harrison and Harrison et al., Compendium of Synthetic Organic Methods , Vols. 1-8 (John Wiley and Sons, 1971-1996), which are incorporated herein by reference in their entirety. Representative hydroxy protecting groups include benzyl and trityl ethers, tetrahydropyranyl ethers, trialkylsilylethers, carbamates and allyl ethers.

Typically hydroxy groups are protected as silyl ethers, but the scope of the present invention is described in Protective groups in Organic Synthesis , 3rd edition, and Copenium of Synthetic Organic Methods , Vols. 1-8, the use of optional hydroxy protecting groups known in the art.

Generally, the phosphine oxide of formula III in tetrahydrofuran is reacted with n-butyllithium typically at about -78 ° C. To this mixture is added a solution of the ketone of formula II in tetrahydrofuran to prepare a compound of formula I. As above, when R ¹ and / or R ⁴ are hydrogen, they are protected with hydroxy protecting groups prior to the coupling reaction. In this case, the hydroxy protecting group is subsequently removed to provide the compound of formula (I).

Synthesis and purification of the compounds of formula III are known and common in the art. See, eg, MR Uskokovic et al ., "Vitamin D Gene Regulation, Structure Function Analysis and Clinical Application," Paris, France, pp 139-145 (1991), DeLuca et al . US Pat. No. 5,086,191. And 5,616,759, US Pat. No. 5,087,619 to Baggiolini, US Pat. No. 5,384,314 to Doran et al., US Pat. No. 5,428,029 to Doran et al., US Pat. European Patent Publication No. EP 0 808,832 A2, Brasitus et al., WO 96/31216, Shiuey et al., J. Org. Chem ., 55: 243-247 (1990) ], Kiegel, J. et al., Tetr . Lett ., 32: 6057-6060 (1991) and Perlman, KL et al., Tetr . Lett ., 32: 7663-7666 (1991).

Scheme I shows a synthetic process for preparing compounds of Formula IA:

In Scheme I, the compound of formula IV is prepared according to the method described in WO99 / 12894 published March 18, 1999 (method for preparing 1,3-dihydroxy-20,20-dialkyl vitamin D3 analogues). It is a known compound prepared by. Compounds of formula IV are converted to compounds of formula V by selective partial reduction of triple bonds and E-double bonds using lithium aluminum hydride in an inert organic acid such as tetrahydrofuran (THF). This reaction is typically carried out by adding the compound of formula IV to a suspension of LiAlH ₄ in THF at 0 ° C or 5 ° C. The reaction mixture is heated under reflux conditions to provide a compound of formula V. Compounds of formula V are converted to ketones of formula VI by oxidation using an oxidizing agent such as pyridinium dichromate. This reaction is generally carried out in halogenated solvents such as methylene chloride at room temperature. The hydroxyl group of the compound of formula VI is then room temperature in an inert solvent such as a halogenated solvent (eg methylene chloride) using a silylating agent such as 1- (trimethylsilyl) imidazole, trimethylsilyl chloride or trimethylsilyl triflate. Protected as a silyl ether of formula (VII). Compounds of formula IIIA react with n-butyllithium and the resulting compounds generally react with compounds of formula VII in tetrahydrofuran at about −78 ° C., and then the silyl protecting group is, for example, in a tetrahydrofuran solvent. Removal with tetrabutylammonium fluoride provides the compound of formula IA '. The free hydroxy group is then acetylated, for example with acetic anhydride in pyridine to give a compound of formula IA. Since secondary hydroxy groups are generally more reactive, they may be selectively acetylated depending on the amount of acetylating agent used and / or reaction conditions used, such as reaction temperature and / or reaction time. Alternatively, both secondary and tertiary hydroxy groups can be acetylated by using excess acetylating agent and longer reaction times.

Similarly, Z-stereomeric analogues or saturated carbon chain analogues of compounds of formula (IA) can be prepared by reduction of compounds of formula (IV) with hydrogen in the presence of a suitable hydrogenation catalyst such as Pd-S or Pd, respectively. The resulting compound can be subjected to similar reaction conditions as shown in Scheme I to prepare the corresponding Z-isomer analogues and saturated carbon chain analogs of the compound of formula (IA).

As shown in Scheme II, compounds of formula II comprising an acetylenic alcohol and varying the alkyl, haloalkyl and cycloalkyl groups of R ² and R ³ are suitable ketones, haloketones (e.g. hexafluoroacetone) and cyclo Ketones can be prepared by condensing and removing protecting groups from acetylide anions derived from a compound of formula VIII, wherein Pg is a hydroxy protecting group:

The compound of formula X is then subjected to similar reaction conditions (ie oxidation, protection and coupling) as in Scheme I above to produce a compound of formula I having an acetylenic linker moiety.

In certain preferred embodiments, the dashed line is a double bond, as represented by Formula IB:

Formula IB

In another preferred embodiment, the linking group L is -CH ₂ -CH ₂ -CH _2- , -CH ₂ -CH = CH-, -CH ₂ -C≡C-, and -CH = CH-CH = CH- It is selected from the configured group.

Preferably R ¹ is an acyl group.

Preferably R ⁴ is hydrogen or an acyl group.

Preferably R ² and R ³ are each independently selected from the group consisting of methyl, ethyl and trifluoromethyl, or R ² and R ³ together with the carbon atom to which they are attached form cycloalkyl.

Numerous different preferred substituents have been presented above and subsequent preferred substituents represent compounds of the invention that are more preferred than those which are not followed by particularly preferred substituents. However, these preferred substituents are generally independent, although some of them are mutually exclusive, and one or more substituents following them represent more preferred compounds than followed by fewer substituents.

Another aspect of the invention provides salts of compounds of formula (I).

While various synthetic methods are available for the preparation of compounds of formula (I), one specific embodiment for preparing compounds of formula (I) is as follows.

Compounds of formula I can be prepared by reacting a compound of formula II with a phosphine oxide compound of formula III:

Formula II

Formula III

Where

Ar ¹ and Ar ² are each independently optionally substituted aryl;

Dotted lines, R ¹ , R ² , R ³ , R ⁴ and L are as defined in the Summary of the Invention.

Preferably, Ar ¹ and Ar ² are phenyl. When R ¹ and / or R ⁴ are hydrogen, the corresponding hydroxy group is preferably protected with a hydroxy protecting group suitable for the coupling reaction conditions prior to the coupling reaction between the ketone of formula II and the phosphine oxide compound of formula III. Do.

Suitable hydroxy protecting groups are known to those skilled in the art, and examples of such hydroxy protecting groups are described in Protective groups in Organic Synthesis , 3rd edition, TW Green and PGM Wuts, John Wiley & Sons, New York, 1999 and Harrison and Harrison et al., Compendium of Synthetic Organic Methods , Vols. 1-8 (John Wiley and Sons, 1971-1996), which are incorporated herein by reference in their entirety. Representative hydroxy protecting groups include benzyl, trityl ether, tetrahydropyranyl ether, trialkylsilyl ether and allyl ether.

Typically hydroxy groups are protected as silyl ethers, but the scope of the present invention is described in Protective groups in Organic Synthesis , 3rd edition, and Copenium of Synthetic Organic Methods , Vols. 1-8, the use of optional hydroxy protecting groups known in the art.

Generally, the phosphine oxide of formula III in tetrahydrofuran is reacted with n-butyllithium typically at about -78 ° C. To this mixture is added a solution of the ketone of formula II in tetrahydrofuran to prepare a compound of formula I. As above, when R ¹ and / or R ⁴ are hydrogen, they are protected with hydroxy protecting groups prior to the coupling reaction. In this case, the hydroxy protecting group is subsequently removed to provide the compound of formula (I).

Synthesis and purification of the compounds of formula III are known and conventional in the art. See, for example, MR Uskokovic et al ., "Vitamin D Gene Regulation, Structure Function Analysis and Clinical Application," Paris, France, pp 139-145 (1991), Teruka et al ., US Pat. Nos. 5,086,191 and 5,616,759. US Pat. No. 5,087,619 to Bakyorini et al., US Pat. No. 5,384,314 to Doran et al., US Pat. No. 5,428,029 to Doran et al., US Pat. No. WO 96/31216, Shiuey et al., J. Org. Chem ., 55: 243-247 (1990), Kigel, J. et al., Tetr . Lett ., 32: 6057-6060 (1991) and Perlman, KL et al., Tetr . Lett ., 32: 7663-7666 (1991).

Scheme 1a shows a synthetic method for preparing compounds of Formula IA:

In Scheme 1a, the compound of formula IV is prepared according to the method described in WO99 / 12894 published March 18, 1999 (method for preparing 1,3-dihydroxy-20,20-dialkyl vitamin D3 analog). It is a known compound prepared by. Compounds of formula IV are converted to compounds of formula V by selective partial reduction of triple bonds and E-double bonds using lithium aluminum hydride in an inert organic acid such as tetrahydrofuran (THF). This reaction is typically carried out by adding the compound of formula IV to a suspension of LiAlH ₄ in THF at 0 ° C or 5 ° C. The reaction mixture is heated under reflux conditions to provide a compound of formula V. Compounds of formula V are converted to ketones of formula VI by oxidation using an oxidizing agent such as pyridinium dichromate. This reaction is generally carried out in halogenated solvents such as methylene chloride at room temperature. The hydroxyl group of the compound of formula VI is then room temperature in an inert solvent such as a halogenated solvent (eg methylene chloride) using a silylating agent such as 1- (trimethylsilyl) imidazole, trimethylsilyl chloride or trimethylsilyl triflate. Protected as a silyl ether of formula (VII). Compounds of formula (IIIa) react with n-butyllithium and the resulting compounds generally react with compounds of formula (VII) in tetrahydrofuran at −78 ° C., and then the silyl protecting group is, for example, tetrahydrofuran in tetrahydrofuran solvent. Removed with butylammonium fluoride to give a compound of formula (IA).

Similarly, Z-stereomeric analogues or saturated carbon chain analogues of compounds of formula (IA) may be prepared by reducing the compound of formula (IV) with hydrogen in the presence of a suitable hydrogenation catalyst such as Pd-S or Pd, respectively. The resulting compound can be subjected to similar reaction conditions as shown in Scheme 1a to produce the corresponding Z-isomer analogues and saturated carbon chain analogs of the compound of formula (IA).

As shown in Scheme 2a, compounds of formula II comprising an acetylenic alcohol and varying the alkyl, haloalkyl and cycloalkyl groups of R ² and R ³ are suitable ketones, haloketones (e.g. hexafluoroacetone) and cyclo Ketones can be prepared by condensing and removing protecting groups from acetylide anions derived from a compound of formula VIII, wherein Pg is a hydroxy protecting group:

The compound of formula X is then subjected to reaction conditions similar to scheme 1a (ie, oxidation, protection and coupling) set forth above to produce compounds of formula I having acetylenic linker moieties.

Usefulness

The compounds of the present invention are useful for the prevention and treatment of many mammalian conditions, which are defined as loss of bone mass. All such situations are referred to as "bone related diseases" and are described in more detail below. In particular, the compounds of the present invention exhibit the prevention and treatment of osteoporosis and osteopenia in mammals without inducing hypercalciuria, hypercalcemia or nephrotoxicity. "Hypercalcemia" is an excess of calcium in serum, which corresponds to higher than about 10.5 mg / dL in humans (and rats). "Excessive calciumemia", which typically has a serum calcium concentration higher than about 12 mg / dl, is mainly associated with emotional instability, confusion, confusion, mental illness, paralysis, and brain death.

Compounds of the present invention include Type I (postmenopausal), Type II (Medical), including those associated with corticosteroid treatment, as well as treatment of osteo dysplasia due to renal dialysis and hyperparathyroidism (eg, for asthma) and Useful for the treatment of type III (old age) osteoporosis. Treatment with the vitamin D ₃ analogs described herein results in increased bone mineral density and provides good quality bone unlike conventional treatments. Thus, the treatments described herein reduce the incidence of fractures and result in faster healing of pre-existing fractures. Such treatment is particularly useful in patients suffering from estrogen withdrawal symptoms (eg, older women) and at other risks of increased fracture rates. Types of treatable fractures include traumatic and osteoporotic fractures such as buttocks, femurs, cuffs, vertebrae, spinal column, ribs, sternum, laryngeal trachea, respiratory tract, radial / vertebrae, tibia, patella, clavicle, pelvis, There are humerus, lower leg, fingers and toes, face and ankle fractures.

The compounds of the present invention are also useful for the treatment of diseases caused by increased levels of parathyroid hormone. In one embodiment, the compounds of the present invention are used in the treatment of renal failure related secondary parathyroidism, in particular to restore or reduce bone loss associated with renal failure. Another aspect includes the treatment of renal dysplasia associated with late stage secondary hyperparathyroidism. Another aspect includes the treatment of primary hyperparathyroidism.

The compounds of formula (I) are also useful for the treatment of neoplastic diseases such as leukemia, colon cancer, breast cancer and prostate cancer.

In general, the compounds of the present invention do not cause the increased calcium levels observed in other vitamin D ₃ analogs such as 1,25 (OH) ₂ vitamin D ₃ to provide improved treatment rates and improved treatment of the disease.

Dosing and Pharmaceutical Compositions

In general, the compounds of the present invention contain about 0.0002 to 0.5 mg / kg body weight / day, preferably about 0.001 to about 0.1 mg / kg body weight / day, more preferably about 0.002 to about 0.02 mg / kg body weight / day, Most preferably in an amount from about 0.005 to about 0.010 mg / kg body weight / day. For humans weighing 50 kg, the daily dosage of the active ingredient is about 0.01 to about 25 μg, preferably about 0.05 to about 10 μg, most preferably about 1.0 to about 10 μg. This amount may be delivered in a conventional pharmaceutical composition by single administration, by multiple administrations or via controlled release, more preferably orally once or twice a day as needed to obtain the most effective results. In certain circumstances, every other day administration may prove suitable for achieving the desired therapeutic response.

The choice of correct dosage and composition and the most appropriate dosage regimen is particularly affected by the pharmacological properties of the formulation, the type and severity of the condition to be treated, and the physical condition and mental sensitivity of the patient. In general, in the treatment of corticosteroid-induced osteopenia, the dose required increases as the dose of corticosteroid increases.

Representative administrations include oral, parenteral (including subcutaneous, intramuscular and intravenous), rectal, oral (including sublingual), lung, transdermal and nasal, most preferably oral. Administration can be continuous or intermittent (such as bolus injection).

A related aspect of the present invention relates to the combination therapy of a compound of formula (I) with other active agents such as bisphosphonates, estrogens, selective estrogen receptor modulators (SERMS), calcitonin or assimilation agents. Examples of bisphosphonates include alendronate, ibandronate, pamidronate, etidronate and risedronate. Examples of SERMS include raloxifene, dihydroraloxyphene and lasopoxifen. Calcitonin includes human and salmon calcitonin. Anabolic agents include parathyroid hormone (PTH) such as hPTH (1-34), PTH (1-84) and parathyroid hormone related proteins (PTHrP) and analogs thereof. Certain analogs of PTHrP are described in “Mono- and Bicyclic Analogs of Parathyroid Hormone-Related Protein. 1. Synthesis and Biological Studies.”, Michael Chorev et al., Biochemistry, 36: 3293-3299 (1997) and “Cyclic analogs of PTH and PTHrP "], WO 96/40193 and US Pat. Nos. 5,589,452 and WO97 / 07815. Other active agents may be administered concurrently with, prior to or after the compound of formula (I), or may be administered according to other methods.

A further aspect of the invention relates to pharmaceutical compositions comprising as an active ingredient a compound of the invention together with a pharmaceutically acceptable non-toxic carrier. As noted above, such compositions are for parenteral (subcutaneous, intramuscular or intravenous) administration, in particular in the form of liquid solutions or suspensions; For oral or oral administration, in particular in the form of tablets or capsules; For pulmonary or intranasal administration, especially in the form of powders, nasal drops or aerosols; And for rectal or transdermal administration.

The compositions of the present invention may be administered in unit dosage form and are known in the art of pharmacy, for example in any of the methods described in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, PA (1985). It can be prepared by. Formulations for parenteral administration may contain sterile water or saline, alkylene glycols such as propylene glycol, polyalkylene glycols such as polyethylene glycol, vegetable oils, hydroxylated naphthalenes, and the like as excipients. Formulations for intranasal administration may be solid and may be aqueous or oily solutions, for example containing excipients such as lactose or dextran or for use in the form of nasal or metered spray solutions. Typical excipients for oral administration include sugar, calcium stearate, magnesium stearate, pregelatinized starch and the like.

Orally administrable compositions may include one or more physiologically compatible carriers and / or excipients and may be in solid or liquid form. Tablets and capsules include, for example, binders such as syrup, acacia, gelatin, sorbitol, tragacanth or poly-vinylpyrrolidone; Fillers such as lactose, sucrose, corn starch, calcium phosphate, sorbitol or glycine; Lubricants such as magnesium stearate, talc, polyethylene glycol or silica; And surfactants such as sodium lauryl sulfate. Liquid compositions include, for example, suspending agents such as sorbitol syrup, methyl cellulose, sugar syrup, gelatin, carboxymethylcellulose or edible fats; Emulsifying agents such as lecithin or acacia; Vegetable oils such as almond oil, coconut oil, cod liver oil or peanut oil; Conventional additives such as preservatives such as butylated hydroxyanisole (BHA) and butylated hydroxytoluene (BHT). Liquid compositions can be encapsulated, for example, in gelatin to provide unit dosage forms.

Preferred solid oral dosage forms include tablets, double hard capsules and soft elastic gelatin (SEG) capsules. SEG capsules are of particular note as they offer distinct advantages over the other two forms (see Seager, H., "Soft gelatin capsules: a solution to many tableting problems"; Pharmaceutical Technology, 9, (1985)). Some advantages of using SEG capsules are that a) the dosage uniformity is optimized in the SEG capsule because the drug is dissolved or dispersed in a liquid that can be accurately administered in the capsule, and b) the drug is dissolved in a water-miscible or oily liquid. Drugs formulated as SEG capsules have good bioavailability because the solution dissolves or emulsions to provide a high surface area drug dispersion when solubilized or dispersed and released into the body, and c) the dry skin of soft gelatin diffuses oxygen Providing a barrier against this prevents degradation of oxidation sensitive drugs during long term storage.

Dry shell formulations typically comprise a concentration of about 40% to 60% gelatin, about 20% to 30% plasticizer (such as glycerin, sorbitol or propylene glycol) and about 30 to 40% water. Other materials may also be present such as auxiliaries, dyes, opacifiers and flavorings. Liquid filler materials are solid drugs dissolved in, or dissolved in, or suspended in suspending agents such as beeswax, hydroxy castol oil or polyethylene glycol 4000 or vehicles such as mineral oil, vegetable oils, triglycerides, glycols, polyols and surfactants. Or liquid drugs in combination thereof.

The following examples are presented to enable those skilled in the art to more clearly understand and to practice the present invention. This is not intended to limit the scope of the present invention but merely to illustrate the present invention.

The following examples are provided to illustrate but not limit the invention.

Example 1

This example shows [1R- (1α (E), 3aβ, 7aα)]-octahydro-7a-methyl-1- [5,5,5-trifluoro-4-hydroxy-4- (trifluoro A method for preparing methyl) -2-pentynyl] cyclopropyl] -4H-inden-4-ol is described.

To a stirred cooled (5 ° C.) suspension of LiAlH ₄ (237.2 mg, 6.25 mmol) in dry THF (6.0 mL) was added powdered NaOMe (338 mg, 6.25 mmol). The mixture was stirred at 5 ° C. under Ar for 15 min and [1R- (1α, 3aβ, 4α, 7aα)]-octahydro-7a-methyl-1- [5,5,5-tri in anhydrous THF (6.0 mL) Treated with a solution of fluoro-4-hydroxy-4- (trifluoromethyl) -2-pentynyl] cyclopropyl] -4H-inden-4-ol (500 mg, 1.25 mmol), followed by 2.5 hours under reflux Boil for a while. After cooling, the mixture was diluted with Et ₂ O (25 mL), quenched by dropwise addition of water (2.0 mL) and 2M NaOH (2.0 mL), and stirred at room temperature for 30 minutes. MgSO ₄ (5 g) was added and stirred for an additional 30 minutes, then the mixture was diluted with Et ₂ O (25 mL) and filtered over Celite (15 g) washed with EtOAc (3 × 20 mL). . Evaporation gave a gum (508 mg), which was purified by flash chromatography (50 g of silica gel, 3.5 cm diameter column, 30% EtOAc in hexanes) to give a 20 mL fraction. Fractions 7-12 were evaporated to yield colorless crystals (486 mg) which were triturated with hexanes and collected by filtration to give the title compound (442 mg, 88%). Melting point 122-123 ° C.

Analytical Calcd for C ₁₉ H ₂₆ F ₆ O ₂ : C, 56.99; H, 6.55; F, 28.47. Found: C, 56.87; H, 6.33; F, 28.69.

Example 2

This example shows [1R- (1α (E), 3aβ, 7aα)]-octahydro-7a-methyl-1- [1- [1- [5,5,5-trifluoro-4-hydroxy- A process for preparing 4- (trifluoromethyl) -2-pentynyl] cyclopropyl] -4H-inden-4-one is described.

[1R- (1α (E), 3aβ, 4α, 7aα)]-octahydro-7a-methyl-1- [5,5,5-trifluoro-4-hydroxy in CH ₂ Cl ₂ (8.0 mL) Pyridinium dichromate (1.25 g, 3.3 mmol) triturated in a stirred solution of -4- (trifluoromethyl) -2-pentynyl] cyclopropyl] -4H-inden-4-ol (400 mg, 1.00 mmol) Was added. The mixture was stirred at rt for 4.5 h, diluted with diisopropyl ether (15 mL) and worked up to afford 395 mg of a colorless gum. 20 ml fractions were collected by flash chromatography (50 g silica gel, 3.5 cm diameter column, 30% EtOAc in hexanes), and fractions 7-12 were evaporated to give the title compound (376 mg, 94%) was obtained.

Analytical calcd. For C ₁₉ H ₂₄ F ₆ O ₂ : C, 57.28; H, 6.07; F, 28.61. Found: C, 57.19; H, 6.25; F, 28.71.

Example 3

This example shows [1R- (1α (E), 3aβ, 7aα)]-octahydro-7a-methyl-1- [1- [5,5,5-trifluoro-4-trifluoromethyl)- A process for preparing 4-[(trimethylsilyl) oxy] -2-pentynyl] cyclopropyl] -4H-inden-4-one is described.

[1R- (1α (E), 3aβ, 7aα)]-octahydro-7a-methyl-1- [1- [5,5,5-trifluoro-4- in anhydrous CH ₂ Cl ₂ (5 mL) A stirred solution of hydroxy-4- (trifluoromethyl) -2-pentynyl] cyclopropyl] -4H-inden-4-one (165 mg, 0.41 mmol) was dissolved in 1- (trimethylsilyl) imidazole (0.5 mL). , 3.4 mmol) and worked up for 5 hours to afford the crude title compound (193 mg). Flash chromatography (25 g silica gel, 20% EtOAc in hexanes) gave the title compound (161 mg, 83%) as an oil.

Analytical calcd. For C ₂₂ H ₃₂ F ₆ O ₂ Si: C, 56.15; H, 6.85; F, 24.22. Found: C, 56.42; H, 6.63; F, 24.37.

Example 4

This example provides a process for the preparation of 3-desoxy-1,25-dihydroxy-20-methyl-23- (E) -ene-26,27-hexafluorouro-21,28-cyclocholcalciferol. Describe.

Horner's reagent [R- (Z)]-[2- [3-[[(1,1-dimethylethyl) -dimethyl-silyl] oxy] -2-methylenecyclohexyl in dry THF (5.0 mL) Den] ethyl] diphenylphosphine oxide (395 mg, 0.872 mmol) was deprotonated with a 1.6 M solution of n-BuLi in hexane (0.55 mL, 0.88 mmol) at −78 ° C. and anhydrous THF (2.0 mL) after 8 minutes. Ketone [1S- [1α (E), 3aβ, 7aα)]-octahydro-7a-methyl-1- [1- [5,5,5-trifluoro-4- (trifluoromethyl) -4 -[(Trimethylsilyl) oxy-2-pentynyl] cyclopropyl] -4H-inden-4-one (170 mg, 0.361 mmol) was reacted for 3 hours and worked up. Flash chromatography (45 g silica gel, 20% EtOAc in hexanes) afforded a gum (215 mg). Was dissolved in THF (3㎖) and, n-Bu ₄ N ⁺ F in THF (2.8㎖) ^- treated with 1.0M solution, which was stirred for 19 hours. After workup, flash chromatography (40 g of silica gel, 40% EtOAc in hexanes) afforded a gum, dissolved in HCO ₂ Me (5.0 mL), filtered through a 0.45 μm filter and evaporated. High vacuum drying (3 hours) gave the title compound (144 mg) as a colorless foam.

Example 5

This example provides a process for the preparation of 3-desoxy-1,25-dihydroxy-20-methyl-23- (Z) -ene-26,27-hexafluoro-21,28-cyclocholecalciferol. Describe.

Horner reagent [R- (Z)]-[2- [3-[[(1,1-dimethylethyl) -dimethyl-silyl] oxy] -2-methylenecyclohexylidene] ethyl in anhydrous THF (3.0 mL) ] Diphenylphosphine oxide (236 mg, 0.5 mmol) was treated with a 1.6 M solution of n-BuLi in hexane (0.32 mL, 0.512 mmol). After 8 minutes ketone [1S- [1α (Z), 3aβ, 7aα)]-octahydro-7a-methyl-1- [1- [5,5,5-trifluoro-4- in THF (2.0 mL) (Trifluoromethyl) -4-[(trimethylsilyl) oxy] -2-pentynyl] cyclopropyl-4H-inden-4-one (117.5 mg, 0.25 mmol) was added and stirring continued for 2.5 hours. Post-treatment gave a gum and was purified by flash chromatography (40 g of silica gel, 20% EtOAc in hexane) to give a gum (120 mg). This was dissolved in THF (2.0㎖), n-Bu 4 N + F in THF (2.0㎖) ^- it was treated with a 1M solution, stirred for 20 hours at room temperature and then worked up. Flash chromatography (40 g silica gel, 40% EtOAc in hexanes) gave the title compound (29 mg) as a colorless foam.

Example 6

This example describes a process for the preparation of 3-desoxy-1,25-dihydroxy-20-methyl-23-phosphor-21,28-cyclocholecalciferol.

Horner reagent [R- (Z)]-[2- [3-[[(1,1-dimethylethyl) -dimethylsilyl] oxy] -2-methylenecyclohexylidene] ethyl] di in THF (5.0 mL) Phenylphosphine oxide (375 mg, 0.828 mmol) was treated with a 1.6 M solution of n-BuLi in hexane (0.51 mL, 0.81 mmol). After 8 minutes [1R- [1α, 3aβ, 7aα)]-octahydro-7a-methyl-1- [4-methyl-4-[(trimethylsilyl) oxy] -2-pentynyl] in THF (4.0 mL) Cyclopropyl-4H-inden-4-one (180 mg, 0.50 mmol) was added and the mixture was worked up after 3.5 hours. Flash chromatography (45 g silica gel, 7% EtOAc in hexanes) gave syrup (273 mg), dissolved in THF (3.3 mL) and solution of n-Bu ₄ N ⁺ F ^- 1.0 M in THF (3.3 mL). Stir for 28 hours and work up. Flash chromatography (45 g of silica gel, 40% EtOAc in hexanes) gave the title compound (114 mg) as a colorless foam.

Example 7

This example describes a process for the preparation of 3-desoxy-1,25-dihydroxy-20-methyl-23-yne-26,27-hexafluoro-21,28-cyclocholecalciferol.

Horner reagent [R- (Z)]-[2- [3-[[(1,1-dimethylethyl) -dimethylsilyl] oxy] -2-methylenecyclohexylidene] ethyl] di in THF (5.0 mL) Phenylphosphine oxide (350 mg, 0.773 mmol) was deprotonated at -78 ° C with 1.6 M solution of n-BuLi in hexane (0.49 mL, 0.784 mmol), and after 8 minutes ketone [1S- (1α, 3aβ, 7aα) )]-Octahydro-7a-methyl-1-[-1- [5,5,5-trifluoro-4-hydroxy-4- (trifluoromethyl) -2-pentynyl] cyclopropyl]- It was reacted with 4H-inden-4-one (158 mg, 0.40 mmol) for 3.0 hours. The crude product was purified on a flash chromatography (silica gel 45g, 20% EtOAc in hexanes) and, n-Bu ₄ N ⁺ F in THF (1.8㎖) ^-, and silyl ride at room temperature a 1M solution for 18 hours Chemistry Flash chromatography ( Purification with 45 g silica gel, 40% EtOAc in hexane) gave the title compound (117 mg) as a colorless foam.

Example 8

This example describes a process for the preparation of 3-desoxy-1,25-dihydroxy-20-methyl-21,28-cyclocholecalciferol.

A magnetically stirred 25 ml three-necked round bottom flask equipped with thermometer, side rubber diaphragm, Claisen connector with nitrogen scrubbing and central rubber diaphragm, [R- (Z)]-2- [3- [ Charged with 0.5640 g (1,246 mmol) of [(1,1-dimethylethyl) -dimethylsilyl] oxy] -2-methylenecyclohexylidene] ethyl] diphenylphosphine oxide. The material was dried under high vacuum, 5 ml tetrahydrofuran was added, the solution was stirred and cooled to -70 ° C. and 0.78 ml (1.246 mmol) of 1.6 M BuLi solution in hexane was added (after initial 0.16 ml addition). Red persisted). The solution was stirred at −70 ° C. for 10 minutes and then [1S- (1α, 3aβ, 7aα)]-octahydro-7a-methyl-1- [1- [4-methyl-4 in 8 ml tetrahydrofuran. A solution of 0.2904 g (0.796 mmol) of -oxy] -2-pentanyl-cyclopropyl] -4H-inden-4-one was added dropwise. When the reaction was actually completed (TLC, 1: 9 ethyl acetate: hexane), the mixture was warmed to -30 ° C., followed by a phosphate buffer of pH 7 (139.4 g dipotassium phosphate and 10 ml of 2M phosphoric acid in 400 ml of water) 12 ML was added dropwise through the central outlet. The mixture was stirred for 5 minutes, then 35 ml of hexane was added and transferred to a separating funnel. The aqueous phase was reextracted with 30 mL of hexanes. The two hexane layers were combined, washed with 20 ml brine, passed through a plug of sodium sulfate, dried and evaporated to yield a colorless syrup. This material is dissolved in hexane. The hexane suspension was filtered through a 25 × 120 mm scintillation column because a white solid was present. After fractionation twice (20 mL each) the mobile phase was changed to 1:79 ethyl acetate: hexanes. Fractions 11-18 (according to TLC in 1:19 ethylacetate: hexane) were combined and evaporated. 0.4202 g (88.1%) of the silylated title compound were obtained.

A 100 ml brown round bottom flask was filled with 0.4202 g of the silylated title compound. To this material was added 5 ml of tetrahydrofuran and 3.5 ml of a 1M tetrabutylammonium fluoride solution in tetrahydrofuran and stirred at room temperature for 17 hours. TLC (1: 1 ethyl acetate: hexane and ethyl acetate) shows one main point. The reaction mixture was then diluted with 13 ml brine, stirred for 15 minutes and transferred to a separatory funnel with 40 ml ethyl acetate. The aqueous layer was reextracted with 20 ml of ethyl acetate. The two organic layers were combined, washed with 5x35 ml of water and once brine, then passed through a plug of sodium sulfate and evaporated to yield 0.3523 g of crystalline white residue. This material was chromatographed on a 25 × 110 mm column using 1: 1 ethyl acetate: hexane as the mobile phase. Fractions 3 to 4 have already crystallized in the tubes. The suspension so obtained was concentrated to a volume of about 5 mL, diluted with hexanes, concentrated and filtered to give 0.2567 g of crystalline title compound.

Analytical Calcd for C ₂₈ H ₄₄ O: C, 81.50; H, 10.75; O, 7.75. Found: C, 81.43; H, 10.69; O, 7.48.

In the table, it tends to be occupied by the unshared fine hydrogen of oxygen.

Example 9

This example describes the synthesis of 3-desoxy-1α-acetoxy-25-hydroxy-20-cyclopropyl-23E-en-26,27-hexafluoro-cholecalciferol.

A 25 ml round bottom flask was charged with 0.1702 g of 3-dexy-1α, 25-dihydroxy-20-cyclopropyl-23E-ene-26,27-hexafluoro-cholecalciferol and 2.85 g of pyridine. After the solution was stirred and cooled in an ice bath, 0.5 ml of acetic anhydride was added and stirring was continued for 1 hour in an ice bath. The solution was then left in the refrigerator overnight. The flask was transferred to an ice bath and 0.2 ml of acetic anhydride was added. After 6 hours the solution was diluted with 10 ml of ethyl acetate and 2 ml of water was added while still immersed in an ice bath. The mixture was stirred for 5 minutes and then transferred to a separatory funnel using 20 mL of water and 20 mL of 1: 4 ethyl acetate: hexanes. The aqueous phase was reextracted with 10 mL of 1: 4 ethyl acetate: hexanes. TLC in 1: 2 ethyl acetate: hexanes showed no product in this second extraction. The initial extract was then washed with 4 × 20 mL of water and 10 mL of brine and then evaporated through a sodium sulfate plug. The residue was dissolved in 1: 4 ethyl acetate: hexanes and flash chromatographed on a 15 × 150 mm column using 1: 4 ethyl acetate: hexanes as the mobile phase to give a 10 mL fraction. Most of the main product (0.1050 g) was included in fraction 3. Fraction 3 still contained traces of the faster moving material observed in fraction 2. Attempt to dissolve the residue at the start of 1: 6 ethyl acetate: hexane crystallization. Thus, a small amount of pentane was added and the mixture crystallized in the refrigerator. The mother liquor was recovered and evaporated to yield 0.0068 g. The crystals were rinsed once with pentane and dried to afford 0.0899 g of the title compound.

[α] _D -30.8 ^o (0.54%, methanol).

NMR (CDCl ₃ ): 2.07 (OAc).

Analytical Calcd: C, 64.27; H, 6.83. Found: C, 64.63; H, 6.93; C, 64.52, H, 6.94.

UV max, nm (absorbance) 121 (0.3639), 250 (0.4591), 262 (0.4486), 244 sh (0.4482).

Example 10

The present invention describes a process for the synthesis of 3-desoxy-1α, 25-diacetoxy-20-cyclopropyl-23E-ene-26,27-hexafluoro-cholecalciferol.

3-degree-1α, 25-dihydroxy-20-cyclopropyl-26,27-hexafluoro-cholalyl 3-deoxyl bottomed flask equipped with a clysen linker and stopper including a magnetic stirrer and a nitrogen purge 0.315 g (0.6 mmol) of ciperol, 60 mg of dimethylaminopyridine and 5 ml of pyridine were charged. The flask was immersed in an ice bath and pyridine was added. After 10 minutes, no starting material was actually observed. After 2 hours, the solution was diluted with 10 ml of ethyl acetate and after 10 minutes while immersed in an ice bath, 2 ml of water was added dropwise. The mixture was stirred for 10 minutes and then transferred to a separatory funnel using 20 mL of water and 20 mL of 1: 4 ethyl acetate: hexanes. The aqueous phase was reextracted with 10 mL of 1: 4 ethyl acetate: hexanes. TLC in 1: 2 ethyl acetate: hexanes showed no product in this second extraction. The initial extract was then washed with 4 × 20 mL of water and 20 mL of brine, then passed through a sodium sulfate plug and evaporated. The residue was dissolved in 1: 6 ethyl acetate: hexanes and flash chromatography on a 25 × 150 mm column using 1: 6 ethyl acetate: hexanes as the mobile phase to give a 20 mL fraction. Pure material was included in fraction 3 and fractions 4 to 6 contained product mixed with more slowly moving material (TLC 1: 2). Thus fractions 4-6 were combined and the residue was rechromatated on a 15 × 150 mm column using 1: 9 ethyl acetate: hexane as the mobile phase to give a 20 mL fraction. Fractions 2 and 3 contained large amounts of product in pure form. These fractions were added to fraction 3 of the first chromatogram and then evaporated. The residue was dissolved in 1: 9 ethyl acetate: hexanes, filtered, concentrated, diluted with pentane and refrigerated. The mother liquor was recovered and the crystals were rinsed with pentane and then dried for 2 hours to yield 0.190 g of the title compound.

NMR (CDCl 3): δ 2.08 and 2.20 (2 OAc).

[α] D-110.3, 0.59% (methanol).

MA 192020: Found C, 63.99; H, 6.62; Calc .: C, 63.78; H, 6.69.

UV max (absorbance) 212 (0.3573), 251 (0.4392), 261 (0.4276).

Example 11

This example describes a method for determining the effect of a compound of the invention for bone assimilation in rats.                 

3 months old rats are ovarian resected and 1, 25-dihydroxy vitamin D ₃ or one of the compounds of the present invention starting at 3 weeks after ovarian resection and continuing until last until 6 weeks after ovarian resection. Administration was once daily. Both the SHAM control group (non-ovariectomized rat) and the OVX control group (ovarian ablation group) received only the vehicle. Blood and urine samples were collected twice at 4 and 6 weeks after ovarian resection, and the amount of serum and urine calcium was measured. At 6 weeks after ovarian resection, the final femoral calcium was measured.

Bone mineral density in the right thigh was measured using a high resolution software package from a QDR-1000W bone density meter (Hologic, Waltan, Mass.). The animals were placed on the scanning plate and scanned at the lying position so that the right leg was perpendicular to the main torso and the tibia was perpendicular to the thigh.

Example 12

This example describes a method for determining the relative in vivo efficiency of a compound of the invention and 1,25- (OH) ₂ vitamin D ₃ .

A standard animal model for postmenopausal osteoporosis, ie the rat ovarian ablation model, can be used to compare the efficiency of the compounds of the invention with 1,25-dihydroxy vitamin D ₃ . Three-month-old rats were ovarian resected and then treated for eight weeks, starting one week after ovarian resection. The drug was orally administered once daily in the migliol (medium chain triglyceride) carrier. Blood and urine samples were collected at the 3 and 6 week time points and bone mineral density (BMD) was measured in vivo at 6 weeks using a dual energy X-ray extinometer (Holologic QDR-4500 ™ bone scanner). It was. At 8 weeks the animals were sacrificed and the lumbar spine and femur were removed for in vitro BMD measurements (Lunar PixiMus® bone scanner) and biomechanical tests for strength. The data for each compound was then measured at the safest dose. The safest amount was defined as not inducing hypercalcemia, which is defined as the amount of serum calcium above 10.0 mg / dl.

Example 13

This example describes a comparison of the in vivo efficiency of compound 27 and 1,25- (OH) ₂ vitamin D ₃ .

A standard animal model for postmenopausal osteoporosis, ie, a rat ovarian ablation model, was used to compare the efficiency of compound 27 and 1,25-dihydroxy vitamin D ₃ (ie, VD ₃ ). Three-month-old rats weighing 285 g were treated with ovarian ablation and then treated for 8 weeks starting at 1 week. The drug was orally administered once daily in the migliol (medium chain triglyceride) carrier. Blood and urine samples were collected at the 3 and 6 week time points, and bone mineral density (BMD) was measured in vivo at 6 weeks using a dual energy X-ray extinometer (Holologic QDR-4500 ™ bone scanner). It was. At 8 weeks the animals were sacrificed and the lumbar spine and femur were removed for in vitro BMD measurements (Lunar PixiMus® bone scanner) and biomechanical tests for strength. The data for each compound was then measured at the safest dose. The safest amount was defined as not inducing hypercalcemia, which is defined as the amount of serum calcium above 10.0 mg / dl.

Table 3 below shows safety (serum calcium, urine calcium) results. All amounts compared were 9.3 mg / dl for 3 weeks serum calcium and 9.8 ± 0.1 mg / dl for 6 weeks. In these amounts, urine calcium output per 24 hour is the same for the VD ₃ 0.4 nmol / kg dose and Compound 27 0.5 nmol / kg dose. Table 4 below shows the efficient parameters (BMD, biomechanics and urine deoxypyridinolin) for the two compounds. At all of the bone sites shown in the table, BMD is significantly higher in animals administered Compound 27 than in animals administered VD ₃ in amounts that provide an equivalent amount of serum calcium. These amounts represent amounts that are expected to provide the maximum efficiency that can be safely attained, and high doses of each compound are known to be hypercalcemia. Urine deoxypyridinolin, a marker of bone resorption, is much lower at compound 27 than VD ₃ at 6 weeks, suggesting that compound 27 has greater ability to inhibit bone resorption. Treatment with Compound 27 results in stronger vertebrae. The failure load, the amount of force required to fracture the L5 vertebrae, was measured by the compression test. Much more force was needed to fracture the vertebrae of animals treated with Compound 27 compared to animals treated with VD ₃ at the safest dose.

Compounds of the present invention have a biological activity comparable to compound 27.

Some details have been set forth in the description and examples for purposes of clarity and understanding of the invention. Of course, variations and modifications are possible to those skilled in the art within the scope of the appended claims. Accordingly, it should be understood that the above description is exemplary and non-limiting. Accordingly, the scope of the invention should be determined by the full scope of equivalents thereof by the appended claims.

Patents, patent applications, and publications cited herein are hereby incorporated by reference in their entirety for all purposes to the same extent as if each individual patent, patent application or publication were individually disclosed.

Claims (38)

A compound of formula (I) or a salt thereof Formula I

Where The dotted line optionally represents a double bond; L is -CH ₂ -CH ₂ -CH _2- , -CH ₂ -CH = CH-, -CH ₂ -C≡C-, -CH ₂ -CH ₂ -C (= O)-, and -CH = CH -CH = CH- is a linking group selected from the group consisting of; R ² and R ³ are each independently alkyl or haloalkyl, or R ² and R ³ together with the carbon atom to which they are attached form cycloalkyl; R ¹ and R ⁴ are each independently hydrogen, alkyl, C ₁ -C ₆ -alkyl-C (O), or silyl ether, carbonate, carbamate or alkyl ether; Provided that at least one of R ¹ and R ⁴ is C ₁ -C ₆ -alkyl-C (O). The method of claim 1, Compounds of Formula (IB) Formula IB

Where R ¹ , R ² , R ³ , R ⁴ and L are as defined in claim 1. The method of claim 1, A compound of formula (I) Formula I

Where L is selected from the group consisting of -CH ₂ -CH ₂ -CH _2- , -CH ₂ -CH = CH-, -CH ₂ -C≡C-, and -CH = CH-CH = CH-; R ¹ , R ² , R ³ and R ⁴ are as defined in claim 1. The method of claim 1, L is selected from the group consisting of -CH ₂ -CH = CH- and -CH ₂ -C≡C-. The method of claim 1, R ¹ is C ₁ -C ₆ -alkyl-C (O). The method of claim 1, R ⁴ is C ₁ -C ₆ -alkyl-C (O). The method of claim 1, R ² and R ³ are each independently selected from the group consisting of alkyl and haloalkyl. The method of claim 1, R ² and R ³ are trifluoromethyl. The method of claim 1, [1R- (1α (E), 3aβ, 7aα)] octahydro-7a-methyl-1- [5,5,5-trifluoro-4-hydroxy-4- (trifluoromethyl) -2- Pentynyl] cyclopropyl] -4H-inden-4-ol; [1R- (1α (E), 3aβ, 7aα)] octahydro-7a-methyl-1- [1- [1- [5,5,5-trifluoro-4-hydroxy-4- (trifluoro Rhomethyl) -2-pentynyl] cyclopropyl] -4H-inden-4-one; [1R- (1α (E), 3aβ, 7aα)] octahydro-7a-methyl-1- [1- [5,5,5-trifluoro-4- (trifluoromethyl) -4-[( Trimethylsilyl) oxy] -2-pentynyl] cyclopropyl] -4H-inden-4-one; 3-decoxy-1α-acetoxy-25-hydroxy-20-cyclopropyl-23E-ene-26,27-hexafluorocholecalciferol; And 3-Dexy-lα, 25-diacetoxy-20-cyclopropyl-23E-ene-26,27-hexafluoro-cholecalciferol Compound selected from the group consisting of. delete delete delete delete delete delete Prevention of bone related diseases selected from the group consisting of hyperparathyroidism, secondary parathyroidism, renal dysplasia and osteoporosis, comprising the compound according to any one of claims 1 to 9 and a pharmaceutically acceptable excipient. Or therapeutic pharmaceutical compositions. delete delete delete A bone related disease selected from the group consisting of hyperparathyroidism, secondary hyperparathyroidism, renal dysplasia and osteoporosis, comprising administering the compound according to any one of claims 1 to 9 to a mammal, except humans. How to treat it. delete A method of treating a bone related disease selected from the group consisting of parathyroid hyperplasia, secondary parathyroid hyperplasia, renal dysplasia and osteoporosis, comprising administering a compound of formula (I) or a salt thereof to a mammal other than a human: Formula I

Where The dotted line optionally represents a double bond; L is -CH ₂ -CH ₂ -CH _2- , -CH ₂ -CH = CH-, -CH ₂ -C≡C-, -CH ₂ -CH ₂ -C (= O)-, and -CH = CH -CH = CH- is a linking group selected from the group consisting of; R ¹ and R ⁴ are each independently selected from the group consisting of hydrogen and alkyl; R ² and R ³ are each independently selected from the group consisting of alkyl and haloalkyl, or R ² and R ³ together with the carbon atom to which they are attached form cycloalkyl. delete delete The method of claim 22, Wherein the compound is a compound of Formula IB: Formula IB

Where R ¹ , R ² , R ³ , R ⁴ and L are as defined in claim 1. The method of claim 22, Wherein the linker L is selected from the group consisting of —CH ₂ —CH ₂ —CH ₂ —, —CH ₂ —CH═CH—, —CH ₂ —C≡C—, and —CH═CH—CH═CH—. The method of claim 22, Method L is a linking group selected from the group consisting of -CH ₂ -CH = CH- and -CH ₂ -C≡C-. The method of claim 22, R ¹ is hydrogen. The method of claim 22, R ¹ and R ⁴ are hydrogen. The method of claim 22, R ² and R ³ are each independently selected from the group consisting of alkyl and haloalkyl. The method of claim 22, R ² and R ³ are both trifluoromethyl. The method of claim 22, The disease is osteoporosis. The method of claim 22, How the disease cures or reduces fracture incidence. The method of claim 22, Mammals, except humans, have an increased risk of fracture due to reduced estrogen levels. The method of claim 22, A mammal, except humans, is a female. The method of claim 22, A method of increasing bone mineral density in mammals other than humans. The method of claim 22, A method of administering a compound of formula (I) or a salt thereof to a mammal, except humans, in combination with bisphosphonates, estrogens, selective estrogen receptor modulators or assimilation agents. delete