JP2003516386A - Treatment of inflammatory bowel disease with vitamin D compounds - Google Patents

Abstract

(57) [Summary] A method for treating inflammatory bowel disease, specifically ulcerative colitis and Crohn's disease is disclosed. The method includes administering a vitamin D compound in an amount effective to treat the disease. Administration of a vitamin D compound inhibits or delays the onset of signs of inflammatory bowel disease in susceptible individuals.

Description

Detailed Description of the Invention

TECHNICAL FIELD The present invention relates to vitamin D compounds, and more particularly to the use of vitamin D compounds for the treatment of inflammatory bowel disease.

BACKGROUND ART Natural hormone 1α-25-dihydroxyvitamin D ₃ and its analog 1α-25
-Dihydroxyvitamin D ₂ is known to be a highly potent regulator of calcium homeostasis in animals and humans, and its activity in cell differentiation has been established. Ostem et al., Pro
c. Natl. Acad. Sci. USA, 84, 2610 (1987). Many structural analogs of these metabolites have been synthesized and tested, including 1α-hydroxyvitamin D ₃ , 1α-hydroxyvitamin D ₂ , various side chain cognate vitamins and fluorinated analogs. Some of these compounds show interesting activity segregation in cell differentiation and calcium regulation.
Differences in this activity appear to be useful in the treatment of various diseases such as renal osteodysplasia, vitamin D resistant rickets, osteoporosis, psoriasis and certain malignant diseases.

Inflammatory bowel disease (IBD) is an immune-mediated disease of unknown etiology that affects the gastrointestinal (GI) tract. There are at least two distinct forms of IBD, ulcerative colitis and Crohn's disease. IBD is a chronic recurrent disease, which most commonly involves inflammation of the terminal jejunum and colon, but these diseases affect many sites throughout the digestive tract. Clearly genetic factors predispose individuals to the development of IBD (Podolosky 1991). In addition, there is reason to believe that the environment contributes to the development of IBD and that vitamin D may be an environmental factor affecting IBD. Since IBD has the highest prevalence in northern environments such as North America and Northern Europe, vitamin D from sun exposure is low in areas where IBD is most frequent (Podolosky 1991, Sonnenberg et al. 1991). The main source of Vitamin D comes from its production via a photolytic reaction in the skin, and Vitamin D from sun exposure is low in the northern environment, especially in winter (Clemens et al. 1982).
, DeLuca 1993). Dietary intake of vitamin D is a problem due to the lack of natural foods rich in vitamin D. 65-75% of patients with weight loss diagnosed with Crohn's disease,
It occurs in 18-62% of patients with ulcerative colitis (Fleming 1995, Geerling et al. 19
98). General and special vitamin deficiencies have been found to occur in IBD patients (Andreassen et al 1998, Kuroki et al 1993). To date, the possible correlation between vitamin D status and the incidence and severity of IBD in humans and animals has not been studied. Anecdotal information suggests that vitamin D status can be an environmental factor affecting IBD morbidity and that a study of its correlation is justified.

Identification of vitamin D receptors in peripheral blood mononuclear cells fueled the early interest of vitamin D as an immune system regulator (Bhalla et al. 1983, Provvedini et al. 1983). In particular, CD4 + Th cells have vitamin D receptors and are therefore targets of vitamin D (
Veldnan et al 2000). Formolytically active vitamin D (1,25-dihydroxycholecalciferol) suppressed the development of at least two experimental autoimmune diseases (Cantor
na et al 1996, Cantorna et al 1998a). In vitro 1,25-dihydroxycholecalciferol inhibited T cell proliferation and decreased the production of interleukin (IL) -2, interferon (ITF) -γ and tumor necrosis factor (TNF) -α (Lemire 1992a
). In vivo infusion of 1,25-dihydroxycholecalciferol is a type 1 helper T (
It was shown to inhibit the delayed type hypersensitivity reaction related to Th1) cell reaction (Lemire et al. 19
91, Lemire et al. 1992a). Vitamin D is a potent regulator of the general and T cell-specific immune system.

In IBD, the immune-mediated attack is on the GI tract (Niessner and Vo
lk 1995, Podolosky 1991). Preferentially Th1 cytokines (IL-2, INF-
(γ, TNF-α) -producing T cells transfer Crohn's disease-like symptoms to naive mice (Aranda et al. 1997, Bregenholt and Claesson 1998), and Th1 cytokine production is also associated with IBD in humans. (Niessner and Volk 1995
)It has been shown. The 1,25 dihydroxycholecalciferol formulation has been shown to suppress the development of other T cell mediated experimental autoimmune diseases (multiple sclerosis and arthritis, Cantorna et al 1996, Cantorna et al 1998a). The hypothesis that vitamin D will suppress the development and progression of IBD (via the production of 1,25-dihydroxycholecalciferol) seems therefore to be credible.

Standard treatments for IBD patients include short-term high-dose and long-term low-dose prednisone use (Podolosky 1991, Andreassen et al 1998). Prednisone and other corticosteroid therapies result in reduced bone mineral density, often leading to high-risk vertebral fracture (Andreassen et al 1997, Andreassen et al 1998). Supplementation of patient vitamin D with corticosteroids has been shown to prevent steroid-induced bone loss (Buckley et al. 1996). The hormonally active forms of Vitamin D (1,25-dihydroxycholecalciferol) are found in laboratory animals (Cantora et al 1998b) and humans (Ongphip).
It has been known to increase bone mineralization when administered to hadhanakul et al. 2000). Thus, a further benefit of vitamin D and / or 1,25-dihydroxycholecalciferol supplementation is also maintenance of bone mineral density.

DISCLOSURE OF THE INVENTION The present invention is a method and method for preventing inflammatory bowel disease (IBD) in susceptible individuals.
IB by administering an effective amount of a vitamin D compound, preferably 1.25 (OH) ₂ D ₃ or an analogue thereof, which prevents the development of BD or reduces the symptoms of IBD.
This is a method of treating D patient. The method involves selecting an IBD patient and administering to the patient a sufficient amount of a vitamin D analog effective to ameliorate the IBD symptoms.

Vitamin D compounds found to be structurally effective in treating IBD are characterized by the general structural formula I:

[0009]

[Chemical 7]

Wherein Y ₁ and Y _{2, which} may be the same or different, are each selected from the group consisting of hydrogen and a hydroxy protecting group, Z ₁ and Z ₂ are both hydrogen or Z ₁ and Z ₂ are both CH ₂ and X ₁ and X ₂ are both hydrogen, or one is hydrogen and the other is O-allyl, O-alkyl, alkyl, hydroxyalkyl or fluoroalkyl, and can adopt α or β coordination, Or together represent an alkylidene group, ═CR ₆ R ₇ , R ₆ and R ₇ may be the same or different and each is selected from the group consisting of hydrogen, alkyl, hydroxyalkyl and fluoroalkyl, or together Represents a (CH2) x- group (x is an integer of 2 to 5), can adopt α or β coordination, and R represents a typical arbitrary side chain known to vitamin D type compounds.

More specifically, R can also represent a saturated or unsaturated hydrocarbon radical having 1 to 35 carbon atoms which may be straight-chain, side-chain or cyclic, and may further comprise one or more substituents, namely hydroxy- or It may also include a protected hydroxy group, fluoro, carbonyl, ester, epoxy, amino or other heteroatom group. A preferred side chain of this type is represented by the structure:

[0012]

[Chemical 8]

In the above formula, the stereochemical center (corresponding to C-20 in steroid numbering) is R or S
Coordination is also possible (ie natural coordination around 20 carbons or 20 epi coordination)
Z in the formula is selected from Y, —OY, —CH ₂ OY, —C≡CY and —CH═CHY,
The double bond may be either cis or trans and Y is selected from hydrogen, methyl, -COR ⁵ and radicals of the structure:

[0014]

[Chemical 9]

Wherein m and n independently represent the integers 0-5 and R ¹ is selected from hydrogen, deuterium, hydroxy, protected hydroxy, fluoro, trifluoromethyl and C 1-5 alkyl. It may be a straight chain or a side chain, and optionally bears a hydroxy or protected hydroxy substituent. In the formula, R ² , R ³ and R ⁴ are independently deuterium, deuterium alkyl, hydrogen, fluoro, , Trifluoromethyl and C1-5 alkyl, which may be linear or branched and optionally bear a hydroxy or protected hydroxy substituent, wherein R ¹ and R ² together represent an oxo group, an alkylidene. Base = CR ²
R ^3, or - (CH ₂₎ p-group (p is integer of 2 to 5) represents, R3 and R4 oxo group together, or - (CH2) q group (q is integer of 2 to 5 R ⁵ represents hydrogen, hydroxy, protected hydroxy, or C1-5 alkyl, and any CH-group at the 20,22 or 23 position in the side chain may be substituted with a nitrogen atom,
Alternatively, any group at the 20, 22 and 23 position, --CH (CH ₃ )-, --CH (R ³ )-or --C
H (R ² )-may be substituted with oxygen or sulfur atom, respectively.

The wavy line to the methyl substituent at C-20 indicates that C-20 is in either the R or S configuration.

A particularly important example of a side chain having a natural 20R configuration is represented by the following structural formulas (a), (b), (
c), (d) and (e), that is, 25-hydroxyvitamin D ₃ (a), vitamin D ₃ (b), 25-hydroxyvitamin D ₂ (c), vitamin D ₂ (d
), The structure of the C-24 epimer (e) of 25-hydroxyvitamin D ₂ .

[0018]

[Chemical 10]

Particularly suitable vitamin D analogs are, without limitation, the following: 1,25-dihydroxyvitamin D ₃ , 1α-hydroxyvitamin D ₃ , 1,25-dihydroxyvitamin D ₂ , 19-nor-1,25-dihydroxyvitamin D ₂ , 26,27-hexafluoro-1,25-dihydroxy Vitamin D ₂ , 1,25-dihydroxy-24 (E) -dehydro-24-homo-vitamin D ₃ , 19-nor-1,25-dihydroxy-21-epi-vitamin D ₃ , 1α-25-dihydroxyvitamin D ₃ triacetate and 25-acetyl-1
α, 25-dihydroxyvitamin D ₃ . In the most preferred form of the invention, compound 1,
It is 25 (OH) ₂ D _3.

The above compound may be present in an IBD therapeutic composition in an amount of about 0.01 μg / gm to about 10% of the composition.
It is present in an amount of 0 μg / mg and is administered topically, transdermally, orally or parenterally at a dose of about 0.01 μg / day to about 100 μg / day.

The preferred dose of the vitamin D compound of the present invention is the maximum that the patient can tolerate and does not develop severe hypercalcemia. If the vitamin D compound is not a 1-hydroxy compound, a particularly advantageous daily dose of the vitamin D compound is 5.0 μg to 50 μg / day per 160 lbs. If the vitamin D compound is a 1-hydroxy compound, the preferred dose is 0.5 to 10 per 160 pounds of patient.
μg / day. If the patient's calcium intake is about 800 mg / day, a dose of 1.25 (OH) ₂ D ₃ above 0.75 μg / day of 160 pounds of patient is not preferred. High doses of 1.25 (OH) ₂ D ₃ are possible and preferred if the patient has a low calcium diet and / or is late at night. In an embodiment of the present invention, 1,2
The dose of 5 (OH) ₂ D ₃ can be as high as 1.5 μg / day per 160 pounds of patient weight. The preferred dose of 1.25 (OH) ₂ D ₃ is 0.5 to 1.0 μg / day per 160 pounds of patient weight.

DETAILED DESCRIPTION OF THE INVENTION As used herein and in the claims, the term “hydroxy protecting group” refers to any group commonly used to temporarily protect hydroxy functionality, such as alkoxycarbonyl, acyl, It refers to groups such as alkylsilyl or alkylallylsilyl (herein simply referred to as "silyl group") and alkoxyalkyl groups. The alkoxycarbonyl protecting group is an alkyl-O-CO- group, such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, t-butoxycarbonyl, benzyloxycarbonyl or allyloxycarbonyl. is there. The term "acyl" means an alkanoyl group having 1 to 6 carbon atoms, all isomers thereof or a carboxyalkanoyl group having 1 to 6 carbon atoms, for example, oxalyl, malonyl, succinyl, glutaryl group,
Alternatively, it means benzoyl or an aromatic acyl group such as halo, nitro or alkyl-substituted benzoyl group. As used herein or in the claims, the term "alkyl" refers to straight or branched chain alkyl radicals having 1 to 10 carbon atoms, and all isomers thereof. Alkoxyalkyl protecting groups include methoxymethyl, ethoxymethyl, methoxyethoxymethyl, or tetrahydrofuranyl and tetrahydropyranyl. Preferred silyl protecting groups are trimethylsilyl, triethylsilyl, t-butyldimethylsilyl, dibutylmethylsilyl, diphenylmethylsilyl, phenyldimethylsilyl, diphenyl-t-butylsilyl and similar alkylated silyl radicals. The term "allyl" means a phenyl-, or an alkyl-, nitro- or halo-substituted phenyl group.

A “protected hydroxy” group is any group described above which is normally used for the primary or permanent protection of hydroxy functionality as already defined, eg silyl,
A hydroxy group protected or derivatized by an alkoxyalkyl, acyl or alkoxycarbonyl group. The terms "hydroxyalkyl", "deuterium alkyl" and "fluoroalkyl" refer to an alkyl radical substituted with one or more hydroxy, deuterium or fluoro groups, respectively.

The term “vitamin D compound” refers to a compound defined by general structural formula I. It should be noted that in the present specification, the term "24-homo" means one methylene group addition at the carbon at position 24 in the side chain, and the term "24 dihomo" means two methylene group additions. . Similarly, the term "trihomo" means the addition of 3 methylene groups. the term"
"26,27-dimethyl" means the addition of a methylene group at the 26 and 27 positions on the carbon.
For example, R ³ and R ⁴ are ethyl groups. Similarly, the term "26,27-diethyl" is 2
This means the addition of two ethyl groups at 6 and 27-position, R ³ and R ⁴ means a propyl group.

In the list of compounds shown below, if an alkylidene or alkyl substituent is attached to the carbon in the 2-position, this particular alkylidene or alkyl substituent should be added in the nomenclature. For example, if the methylene group is an alkylidene substituent,
The term "2-methylene" should lead to each named compound. If the ethylene group is an alkylidene substituent, the term "2-ethylene" should lead to each named compound. Similarly, if the methyl or ethyl group is an alkyl substituent,
The term "2-methyl" or "2-ethyl", respectively, should precede each named compound and so on. Also, if Z ₁ and Z ₂ in Structural Formula I are both hydrogen, the term “19 nor” leads to the respective named compound. Furthermore, if the methyl group added to the 20-position carbon is in its epi or unnatural configuration, the term "20 (S)" or "
“20-epi” should be included in each nomenclature compound that follows. The nomenclature compound may be of the vitamin D ₂ and / or D ₄ type if desired.

[0026]   A special and preferred example of the vitamin D compound of structural formula I is when the side difference is unsaturated, 1α-Hydroxy-22-dehydrovitamin D₃, 1,25-dihydroxy-22 dehydrovitamin D₃, 1,24-dihydroxy-22 dehydrovitamin D₃, 24-Homo-1,25-dihydroxy-22 dehydrovitamin D₃, 24-dihomo-1,25-dihydroxy-22 dehydrovitamin D₃, 24-Trihomo-1,25-dihydroxy-22 dehydrovitamin D₃, 26,27-Dimethyl-24-homo-1,25-dihydroxy-22 dehydrovitamin D ₃ , 26,27-Dimethyl-24-dihomo-1,25-dihydroxy-22 dehydrovitamin
D₃, 26,27-Dimethyl-24-trihomo-1,25-dihydroxy-22 dehydrovitamin
D₃, 26,27-Diethyl-24-homo-1,25-dihydroxy-22 dehydrovitamin D ₃ , 26,27-diethyl-24-dihomo-1,25-dihydroxy-22 dehydrovitamin
D₃, 26,27-diethyl-24-trihomo-1,25-dihydroxy-22 dehydrovitamin
D₃, 26,27-dipropyl-24-homo-1,25-dihydroxy-22 dehydrovitamin
D₃, 26,27-dipropyl-24-dihomo-1,25-dihydroxy-22 dehydrovitamin
D₃, 26,27-dipropyl-24-trihomo-1,25-dihydroxy-22 dehydrovita
Min D₃Is.

[0027] When a special and preferred examples of vitamin D compounds of structural formula I side difference is saturated, 1.alpha.-hydroxy vitamin D _3, 1,25- dihydroxyvitamin D _3, 1,24- dihydroxyvitamin D ₃ , 24-homo-1,25-dihydroxyvitamin D ₃ , 24-dihomo-1,25-dihydroxyvitamin D ₃ , 24-trihomo-1,25-dihydroxyvitamin D ₃ , 26,27-dimethyl-24-homo- 1,25-dihydroxyvitamin D _3, 26,27- dimethyl-24-dihomo -1,25- dihydroxyvitamin D _3, 26,27- dimethyl-24-Torihomo -1,25- dihydroxyvitamin D _3, 26, 27 - diethyl-24-homo -1,25- dihydroxyvitamin D _3, 26,27- diethyl-24-dihomo -1,25- dihydroxyvitamin D _3, 26,27- diethyl -24- Torihomo -1,25- Hydroxyvitamin D _3, 26,27- dipropyl-24-homo -1,25- dihydroxyvitamin D _3, 26,27- dipropyl-24-dihomo -1,25- dihydroxyvitamin D _3, 26,27- dipropyl -24 - Torihomo -1,25- dihydroxy vitamin D _3.

The synthesis of the vitamin D compound having the basic structure I is a conventional general method, that is, the bicyclic Windaus-Grundmann type ketone II and the allyl phosphine oxide III.
With the corresponding vitamin D analog IV, if desired, followed by deprotection at C-1 and C-3 in the latter compound.

[0029]

[Chemical 11]

In Structural Formulas II, III and IV, X ₁ , X ₂ , Y ₁ and Y ₂ , Z ₁ and Z ₂ and R represent the groups already defined, and Y ₁ and Y ₂ represent a hydroxy protecting group. It is understood that is preferably, sensitive or appears to be sensitive, or the functionality in R that interferes with the condensation reaction is appropriately protected, as is well known to those skilled in the art. The process described above is an application of the convergent synthetic concept, which has been effectively applied to the synthesis of vitamin D compounds (eg Lythgoe et al., J. Chem. Soc. Perkin Trans. I, 590 (1978), Lythgoe, Chem. . Soc. Rev. 9,
449 (1983), Toe et al., J. Org. Chem. 48, 1414 (1983), Baggiolini et al., J. Or.
g. Chem. 51, 3098 (1986), Sardina et al., J. Chem. 51, 1264 (1986), J. Org.
Chem. 51, 1269 (1986), DeLuca et al., U.S. Pat.No. 5,086,191, DeLuca et al.
(U.S. Pat. No. 5,536,713).

Hydroindanones of general structure II are known or can be synthesized by well known methods. Particularly important examples of such known bicyclic ketones are the above-mentioned immediate chains (a), (b), (c
) And (d), that is, the ketone of 25-hydroxy Grundmann (
f) (Baggiolini et al., J. Org. Chem. 51, 3098 (1986)), Grundmann ketone (g) (Inhoffen et al., Chem. Ber. 90, 664 (1957)), 25-hydroxywindausketone (h). ) (Baggiolini et al., J. Org. Chem. 51, 3098 (1986)) and Windaus ketone (i) (Windaus et al. Ann. 524, 297 (1936)).

[0032]

[Chemical 12]

Regarding the synthesis of the phosphine oxide required for general structural formula III, the synthetic route is Perlm
As described by an et al., methyl quinate derivatives, readily available on the market (1R, 3
A method starting from R, 4S, 5R)-(-) quinic acid has been developed (Tetrahedron Let
32, 7663 (1991) and DeLuca et al., US Pat. No. 5,086,191).

The overall synthetic process of Compound I is described in US Pat. No. 5,9,93 issued Aug. 31, 1999.
45,410, "2-Alkyl-19-nor-Vitamin D Compounds" has a more complete description, the specification of which is hereby incorporated by reference.

The present invention will be further described by the following examples. This example demonstrates that vitamin D deficiency exacerbates IBD symptoms in IL-10KO mice. Vitamin D deficiency exacerbates the symptoms of intestinal inflammation in animal models. These data predict that both forms of IBD (ulcerative colitis and Crohn's disease) are compatible with prescribing 1.25 (OH) ₂ D ₃ and other vitamins themselves.

[0036]

【Example】

Recently, transgenic animals have been developed in which IBD symptoms develop endogenously. One of the best animal models for Crohn's disease is IL-10 knockout (KO
) Mouse (Kuhn et al. 1993, MacDonald 1994). In a typical animal facility, IL-1
0KO mice develop enteritis within 5-8 weeks of survival (Kuhn et al. 1993). IL-10
Approximately 30% of KO mice die as a result of severe anemia and weight loss (Kuhn et al. 1993).
. The enteritis that develops in IL-10KO mice is due to the uncontrolled immune response to normal microflora, since no disease develops in abacterial IL-10KO mice. Furthermore, mice bred in specific pathogen-free facilities develop moderate disease that does not result in mouse death (Kuhn et al. 1993). IL-10K as an IBD model
There are constraints involved in O-mouse studies. If Vitamin D was a regulator of IL-10 production, the results in this animal model would not indicate that it would appear to occur in a "normal" immune response. However, Crohn's patients show similar symptoms,
There is suppression of IL-10 production and is effectively treated with IL-10 (Narula et al. 19
98).

Materials and Methods Mouse. Age and Gender Match C57B from Pennsylvania State University Breeding Colonies
L / 6 IL-10KO and wild type (WT) mice. Breeding vs. Jackson Laboratory (B
ar Harbor, ME). The Pennsylvania State University animal facility was specific pathogen-free and therefore bred IL-10KO mice were effective. Pennsylvania State University Animal Care and Use Committee Institute (Pennsylvania)
1/25 at State University Institutional Animal Care and Use Committee)
It was reviewed and approved on / 99. IACUC # number 98118-A0.

Diets Females at the second week of gestation were selected from a single pool of breeding females fed a commercial mouse diet and randomly divided into two groups. Starting from a pregnancy dam on a vitamin D deficient diet,
Weanlings were allowed to be vitamin D deficient until 5 weeks of age (Cantorna et al. 1996).
All mice were fed a laboratory-made artificial diet (Modification of Yang et al. 1993, Smith et al. 1987). Mice were vitamin D deficient, vitamin D sufficient or 1,25-dihydroxycholecalciferol supplement. Mice were kept under yellow light to prevent vitamin D synthesis in the skin. Vitamin D until weaning in all mice
It was lacking.

Three-week-old vitamin D deficient mice were randomly assigned to the various treatment groups described below. 1,25 (OH) ₂ D ₃ treatment for another experimental autoimmune disease was most effective at high dietary calcium (1 g calcium / 100 g diet), so all mice were fed a high calcium diet (Cantorna et al 1999). The experimental diet was freshly prepared and replaced every 2-3 days during the experimental period. 1,25-Dihydroxycholecalciferol (1,25 (OH) ₂ D ₃ ) Formulation To ensure that a mouse eats all 1,25 (OH) ₂ D ₃ given, 8 g of diet was given. The containing food cups were changed every other day (completely eaten) during each experiment (Cantorna et al 1996, Cantorna et al 1998a). To monitor vitamin D toxicity, 1.25 (OH) ₂ D ₃ -supplemented mice were observed daily for signs of hypercalcemia. Symptoms of hypercalcemia monitored daily included general health and weight loss.

(Vitamin D Treatment) In the first experimental design, 3-week-old vitamin D-deficient mice were maintained in a vitamin D-deficient state or switched to an experimental diet containing 5.0 μg of cholecalciferol / d (vitamin D). Either). The severity of IBD development was compared between vitamin D deficient and vitamin D sufficient mice.

In the second series of experiments, 3-week-old vitamin D-deficient mice were divided into two groups. One group of mice maintained a vitamin D deficient diet, the other group 0.005 μg / d 1
, 25 (OH) ₂ D ₃ was replenished. Vitamin D deficient and 1.25 (OH) ₂ D ₃ supplemented mice were killed at 9 weeks of age. The other group was supplemented with 0.005 μg / d of 1.25 (OH) ₂ D ₃ . Vitamin D deficient and 1.25 (OH) ₂ D ₃ supplemented mice were killed 4 weeks later at 9 weeks of age.

In the third experimental design, the 1.25 (OH) ₂ D ₃ regimen was initiated at the first signs of IBD symptoms (diarrhea, 7 weeks of age). Seven-week-old mice lacking vitamin D were divided into two groups.
Vitamin D deficiency was maintained in the first group, and 0.005 μg / d of 1,25 (O
H) ₂ D ₃ was replenished. Mice were treated for 2 weeks and 9 week old mice were killed.

Dietary Restriction A series of restricted feeding experiments was performed due to the dramatic weight loss and mortality of vitamin D deficient IL-10KO mice. Three groups of mice were used in this experiment. All mice for this experiment were maintained on vitamin D deficiency for the first 5 weeks of survival (the earliest sign of weight loss). At the 5th week, vitamin D deficient IL-10KO mice were divided into two groups. Half of the mice were maintained on vitamin D deficiency and the other half were switched to a vitamin D-sufficient diet containing 5.0 μg / d of cholecalciferol. Furthermore, the vitamin D-deficient WT mouse group was switched to a diet containing cholecalciferol in a diet of 5.0 μg / d. Vitamin D deficient IL-10KO Foods eaten by mice were weighed daily to obtain vitamin D
Sufficient IL-10KO and WT mice have vitamin D-deficient IL-10KO mice before 2
A restricted diet containing the amount of food eaten for 4 hours was provided.

(Serum measurement) Mice were exsanguinated at the age of 5 weeks, and hemoglobin, calcium and red blood cell count were measured at the end of the experiment. Serum was collected every 2 weeks and serum calcium was measured (normal values in mice are 2.00 to 2.75 mmol / L). Vitamin D deficiency was monitored by serum calcium assay (serum calcium less than 1.75 mmol / L). Calcium (5
87-A) and hemoglobin (525-A) colorimetric kits are available from Sigma Chemical Co. (S
t. Louis, MO). Red blood cells were counted using a hemocytometer.

IBD Severity Diarrhea incidence-related mortality was recorded in IL-10KO and WT mice. further,
The small intestine was removed and weighed. The jejunum of IL-10KO mice was macroscopically distended and was used by others to monitor IBD symptoms in mice (Kuhns et al. 1993). The jejunum of SI was stored in 100 g / L formalin in phosphate buffered saline and sent to Penn State Diagnostic Laboratory for sectioning and staining with hematoxylin and eosin. Four or more paraffin sections (4 microns) from each mouse were evaluated using the exact procedure described by Kuhns et al. (1993). The degree of inflammation of the sections was blindly evaluated on a scale of 0 to 5. No inflammation was 0, few inflammatory cells were 1, moderate inflammation was 2, abscess formation was 3, abscess formation with general inflammatory cells was 4, and many inflammations in the entire section were 5.

(Statistical Analysis) The experiment was repeated as necessary, and when possible, the numerical value was reported as an average from multiple experiments. A two sample test for binomial proportions was used for the statistical analysis of the percentage values shown in Figure 1 as described (Rosner 1986). Weight and weight gain were analyzed by repeated measures ANOVA using simple contrasts comparing diet groups (main effects). The data were subjected to binary ANOVA using diet and IL-10 genotype as grouping factors. All post hoc multiple comparisons were performed using Fisher's protected least significant difference test. Machine Tok Computer Statistics Program (Statview S
Tudent, Abacus Concept, Berkeley, CA) was used to compare the numerical values, and a value of P <0.05 was considered significant.

(FIG. 1) Vitamin D deficiency induces mortality in IL-10KO mice. Vitamin D deficient IL-10KO weanling mice were randomly divided into two groups. Vitamin D in one group
Remained deficient (-D, n = 26), 5.0 μg cholecalciferol in the other group
The same diet containing / d was fed for the rest of the experiment (+ D, n = 10). Vitamin D deficient WT (-D, n = 20) mice were used in these experiments. Vitamin D
Deficient IL-10KO mice died following the development of diarrhea. No diarrhea developed or died in vitamin D-deficient WT and vitamin D-sufficient IL-10KO mice.

(FIG. 2) Growth curves of vitamin D deficient and fully IL-10KO mice, vitamin D deficient WT mice. Vitamin D deficient IL-10KO weanling mice were randomly divided into two groups. Vitamin D deficiency in one group (-D, n = 14 at the beginning of the experiment, n = at the end)
5) was maintained and the other group was fed the same diet containing 5.0 μg cholecalciferol / d for the rest of the experiment (+ D, n = 7). Vitamin D deficiency WT (-
D, n = 9) mice were used for these experiments. Vitamin D enough IL-10KO
Mice grew faster than Vitamin D deficient IL-10KO mice. Growth of Vitamin D deficient WT mice was suppressed but remained constant over a 12 week period (+
D WT mice were significantly lighter at 7 to 11 weeks of age than + D IL-10KO mice, P <0.05), and vitamin D deficient WT mice weighed well with vitamin D sufficient for 12 weeks. did. Vitamin D-10 KO mouse (+ D IL
Significantly lighter than -10 KO mice, P <0.05, suffers from severe wasting disease that results in growth arrest and weight loss at 6 weeks, which inevitably results in mouse death (12).
Until week n = 5). Values are mean ± SEM.

Results Mortality of Vitamin D Deficient IL-10KO Mice FIG. 1 shows that vitamin D deficient IL-10KO mice started to die at 7 weeks of age, and by the 9th week of age 58% of vitamin D deficient IL-10KO mice. Died (15 out of 26 total)
The animal died). After 9 weeks of age, vitamin D-deficient IL-10KO mice continued to weaken and the mortality rate increased. In contrast, vitamin D-sufficient IL-10KO (
The n = 10) mice and the vitamin D deficient WT (n = 20) mice appeared healthy even at 13 weeks of age.

Vitamin D-deficient IL-10KO mice grew slower than vitamin D-sufficient IL-10KO and vitamin D-deficient IL-10WT mice (FIG. 2).
Vitamin D-deficient WT mice grew slower than vitamin D-sufficient IL-10KO mice, but by 12 weeks of age both vitamin D-sufficient IL-10KO and vitamin D-deficient TW mice were of similar size. The growth of the vitamin D deficient IL-10KO mice was stopped by the 6th week and thereafter, and was significantly smaller than that of the vitamin D deficient WT mice (FIG. 2). At 9 weeks of age, vitamin D deficient IL-10KO mice began to lose their appetite and lost weight more rapidly over the next 3 weeks. Subsequent experiments were completed at 9 weeks to avoid unnecessary pain in IL-10KO mice. Vitamin D deficient IL-10KO mice died of a debilitating condition followed by diarrhea.

Vitamin D deficiency, 1,25-dihydroxycholecalciferol supplemented IL-1
IBD Symptoms in 0KO Mice Vitamin D deficient WT and IL-10KO mice were 9 weeks old lighter in weight than corresponding mice supplemented with 1.25 (OH) ₂ D ₃ (Table 1). Vitamin D deficiency IL-1
The weight of 0KO mice was lighter than in previous experiments (FIG. 2); however, in this case it was consistent with the rapid weight loss previously observed with vitamin D-deficient IL-10KO mice. As expected, serum calcium levels in 1.25 (OH) ₂ D ₃ -supplemented mice were significantly higher than vitamin D-deficient mice (P <0.05) (Table 1).
). Hemoglobin levels and red blood cell count is normal, vitamin D-deficient mice, vitamin D sufficiency mice, and 1,25 (OH) ₂ D ₃ different replenishment IL-10KO and WT mice did (data not disclosed).

WT mice that were vitamin D deficient and satisfactory showed no signs of inflammation or abnormalities in SI. Vitamin D deficient IL-10KO mice have 1,25
SI was significantly more inflammatory than in mice with (OH) ₂ D ₃ supplementation or vitamin D sufficiency (P <0.05, Table 1 and data not disclosed). Vitamin D deficiency IL-10
KO mice were the smallest in size, but autopsy showed that they were extremely large SI.
It was shown to have.

Short-term 1,25-dihydroxycholecalciferol treatment and IBD severity There was no significant difference in body weight of mice 2 weeks after 1,25-dihydroxycholecalciferol treatment (data not shown). However, vitamin D deficiency IL-10KO
The SI of the mice was increased, and was significantly higher than that of the IL-10KO mice supplemented with 1,25 (OH) ₂ D ₃ , vitamin D deficient WT mice, and WT mice supplemented with 1,25 (OH) ₂ D ₃ (P <0. .05) (Table 2). In fact, vitamin D deficient IL-10K
The SI of O mice is 9.9% of the total body weight, which is more than twice the normal SI (about 5%, Table 2).
). Inflammation of the small intestine of IL-10KO mice was reduced by 1.25 (OH) ₂ D ₃ treatment for about 2 weeks.

Dietary Restriction and Vitamin Deficiency and IBD Symptoms To exclude the possibility that weight loss and non-vitamin D deficiency are associated with observed IBD symptom progression, vitamin D-sufficient IL-10KO and WT mice. Food intake was restricted (Table 3). Dietary restriction is vitamin D-sufficient IL-10K
Successfully reduced body weight in O and WT mice, but with vitamin D deficient IL
-10 KO mice were still significantly smaller (P <0.05, Table 3). IL-10
KO mice were markedly morbid by 9 weeks in this experiment and were already severely debilitated. Dietary restriction did not change IBD symptoms in vitamin D-sufficient mice. Diet-restricted vitamin D-sufficient IL-10KO mice did not develop or even die the overt enterocolitis found in vitamin D-deficient IL-10KO mice. The SI of vitamin D-sufficient diet-restricted IL-10KO mice did not differ from previous experiments or when compared to WT controls (Table 3). Histopathology confirmed the weight measurements in Table 3 (data not disclosed). Early symptoms of IBD in vitamin D deficient IL-10KO mice were associated with vitamin D deficiency and not with reduced energy or food uptake.

[0055]

[Table 1] 1. All mice were vitamin D deficient (-D) for the first 5 weeks of survival. At week 5 the mice were divided into two groups; half of them were supplemented with 0.005 μg / day 1.25 (OH) ₂ D ₃ for 4 weeks. Values are mean ± SEM. * Significantly different from the diet-matched group, P <0.05. 2. IL = interleukin; KO = knockout; -D = vitamin D deficiency;
_{1,25 (OH) 2 D 3 =} 1,25- dihydroxy cholecalciferol; WT = wild-type.

[0056]

[Table 2] 1. All mice were vitamin D deficient (-D) for the first 7 weeks of survival. At the age of 7 weeks, vitamin D deficient IL-10KO mice begin to show inflammatory symptoms of small intestine (diarrhea and weight loss). 7-week-old IL10KO and WT mice were divided into two groups;
Half of them were supplemented with 0.25 (OH) ₂ D ₃ at 0.2 μg / day for 2 weeks. Values are mean ± S
EM. * P <0.005, significantly greater than all other groups. 2. IL = interleukin; KO = knockout; -D = vitamin D deficiency;
_{1,25 (OH) 2 D 3 =} 1,25- dihydroxy cholecalciferol; WT = wild-type.

[0057]

[Table 3] 1.5-week-old vitamin D-deficient mice were divided into groups, one was continued with a vitamin D-free diet (-D), and the other was switched to a diet supplemented with 5.0 μg / day cholecalciferol (+ D) for 4 weeks. . + D mice had vitamin D deficient IL 24 hours earlier
Dietary uptake was limited only to the amount ingested by -10KO mice. Values are mean ± S
EM. * P <0.005, significantly different from all other groups. 2. IL = interleukin; KO = knockout; -D = vitamin D deficiency;
+ D = 1,25 (OH) ₂ D ₃ sufficient; WT = wild type.

Observations Vitamin D deficiency exacerbates the symptoms of enterocolitis in IL-10KO mice, but treatment with 1,25-dihydroxycholecalciferol for only 2 weeks ameliorate the IBD symptoms in these mice. These findings demonstrate that vitamin D status is an important factor in determining the onset of IBD, and further vitamin D as a physiological regulator of IBD. This is the first experimental proof and shows a link between vitamin D status and IBD.

The progression of IBD over time in vitamin D deficient IL-10KO mice is comparable to that of IBD progressing in IL-10KO mice housed in normal animal facilities (Kuen (Ku
hn) et al., 1993). It is possible (though unlikely) that the microbiota in the digestive tract of IL-10KO mice are disturbed during vitamin D deficiency, resulting in the disease-causing microorganisms multiplying and causing disease. Experiments testing this possibility can be performed in vitamin-deficient sterile mice, but in the absence of microbiota, enterocolitis will probably not develop. More likely, the microbiota does not change in response to vitamin D status, but instead changes the immune response in the absence of vitamin D, leading to more severe IBD in IL-10KO mice.

Accumulating evidence suggests that vitamin D is a modulator of CD4 + T cells, which is responsible for autoimmune disease (Cantoma)
Et al., 1996; Kantoma et al., 1998c). One possible mechanism of vitamin D action lies in the negative regulation of CD4 + T cells and is responsible for these IBDs. Vitamin D has been shown to directly inhibit the effector function of CD4 + T cells both in vitro and in vivo (Cippitelli and Santoni).
antoni), 1998; Lemire 1992). Another possibility is that vitamin D is a positive regulator of T cells or other cells that inhibits the induction or function of IBD-causing T cells. Two possible targets of vitamin D are transforming growth factor (TGF) β1 and IL-4 secreting cells (Kantoma et al., 1
998c). Increased production of TGF-β1 and IL-4 has been shown to occur in vivo in mice treated with 1,25-dihydroxycholecalciferol (Kantoma et al., 1998c). Furthermore, the production of TGF-β1 and IL-4 is associated with inhibition of T cell effector function and suppression of many autoimmune diseases (Gryo (Gr
Oux) et al., 1997). Vitamin D regulation of the immune system is probably complex and involves multiple targets, which together explain the mechanism by which 1,25-dihydroxycholecalciferol inhibits IBD progression.

The standard treatment for IBD patients is to use high doses of prednisone in the short term,
Consisting of long-term, low-dose use (Andreassen et al., 19
98; Podolosky 1991). Prednisone and other corticosteroid therapies reduce bone mineral density, often resulting in the risk of vertebral fracture (Andreasen et al., 1997; Andreasen et al., 1998). Vitamin D supplementation in patients with corticosteroids has been shown to prevent steroid-induced bone loss (Buckley et al., 1996). Vitamin D (1.25
-The hormonally active form of dihydroxycholecalciferol was tested in experimental animals (Kantoma et al., 1998b) and in humans (Ongphiphadakul).
hanakul) et al., 2000) is known to increase bone mineralization. Thus, a further benefit of vitamin D and / or 1,25-dihydroxycholecalciferol supplementation is in maintaining bone mineral density.

This data suggests that 1,25-dihydroxycholecalciferol and its analogs are new effective therapeutic agents for IBD patients. 1,25-
A possible limitation of dihydroxycholecalciferol treatment is hypercalcemia, and as a result it can. Thus, great promise is for vitamin D analogs in combination with standard therapeutic agents. Standard therapeutic agents often work well, but also have many side effects; for example, bone loss, which is vitamin D.
The analog should reverse or completely block. Vitamin D analogs in combination with corticosteroids or sulfasalazine can reduce the effective dose of these drugs and limit side effects, proving to be a new and effective therapeutic agent for human IBD. .

For therapeutic purposes, the novel compounds of the present invention as defined by formula I are suitable for pharmaceutical application as a solution in a harmless solvent or as an emulsion, suspension or dispersion in a suitable solvent or carrier. It can be formulated as a liquid or as a pill, tablet or capsule with a solid carrier by methods well known in the art.
All such formulations include other pharmaceutically acceptable non-toxic additives such as stabilizers,
It may contain anti-oxidants, binders, colorants or emulsifying or taste-improving agents.

The compound may be administered orally, topically, parenterally or transdermally. Advantageously,
The compound may be injected, or by intravenous infusion or a suitable sterile solution, or in liquid or solid dosage form via the gastrointestinal tract, or in the form of a cream, ointment, patch or similar vehicle suitable for transdermal administration. It can be administered. The daily dose of the compound is from 0.01 μg to 100 μg, which is suitable for therapeutic purposes, but such dose corresponds to the activity of the particular compound used, the disease to be treated, its severity and the reaction of the subject, Adjust as is well understood in the art. Appropriate administration of each compound alone or in combination with graded doses of other active vitamin D compounds-eg 1α-hydroxyvitamin D ₂ and / or D ₃ in combination with 1α, 25-dihydroxyvitamin D ₃ It is possible-in this case it has proved to be advantageous to differentiate between the extent of bone mineral recruitment and the stimulation of calcium transport.

The composition for use in treating IBD comprises an effective amount of one or more vitamin D compounds as defined by formula I above as active ingredients and a suitable carrier. An effective amount of such a compound for use in accordance with the invention is from about 0.01 μg to about 100 compositions.
μg and may be administered topically, transdermally, orally or parenterally in a daily dose of about 0.01 μg to about 100 μg.

The compound may be formulated as a cream, lotion, ointment, topical patch, pill, capsule or tablet, or as a solution, emulsion, dispersion or suspension in a pharmaceutically harmless acceptable solvent or oil. Such formulations may further comprise other pharmaceutically harmless or beneficial ingredients such as stabilizers, antioxidants, emulsifiers, colorants, binders or taste improvers.

The formulations of the present invention thus comprise an active ingredient together with a pharmaceutically acceptable carrier and any other therapeutic ingredients. The carrier must be “acceptable” in the sense of being compatible with the other ingredients of the formulation and not injurious to its recipient.

Formulations of the invention suitable for oral administration may be in the form of capsules, sachets, tablets or lozenges, each containing a predetermined amount of active ingredient; in the form of powder or granules; aqueous liquid or non-aqueous. It can be in the form of a liquid solution or suspension; or in the form of an oil-in-water emulsion or a water-in-oil emulsion.

Formulations for rectal administration may be in the form of suppositories which contain the active ingredient and a carrier such as cocoa butter or an enema.

Formulations suitable for parenteral administration conveniently consist of a sterile oily or aqueous active ingredient formulation, which is preferably isotonic with the blood of the recipient.

Formulations suitable for topical administration include liquid or semi-liquid formulations such as liniment,
Lotions, coatings, oil-in-water or water-in-oil emulsions, such as creams, ointments or pastes; or solutions or suspensions, such as drops; or sprays.

The formulations may conveniently be presented in dosage unit form and may be prepared by any of the methods well known in the art of pharmacy. A "dosage unit" is a unit dose, that is, a single dose that can be administered to a patient as a physically and chemically stable unit dose, either the active ingredient itself or a solid or liquid pharmaceutical diluent or carrier therewith. And a mixture with.

[Brief description of drawings]

FIG. 1 1.25 (OH) ₂ D ₃ deficient interleukin-10 wild type mice (IL-10Wt) compared to 1.25 (OH) ₂ D ₃ deficient (−D) maintenance or 1.25 (OH) ) is a graph showing the mortality ₂ D ₃ supplement (+ D) or interleukin-10 knockout mice (IL-10KO).

FIG. 2 1.25 (OH) ₂ D ₃ compared to 1.25 (OH) ₂ D ₃ deficient IL-10Wt mice.
FIG. 9 is a graph showing growth curves of IL-10KO mice that were either depleted (−D) maintained or 1.25 (OH) ₂ D ₃ supplemented (+ D).

─────────────────────────────────────────────────── ─── Continuation of front page (51) Int.Cl. ⁷ Identification code FI theme code (reference) // C07C 401/00 C07C 401/00 (31) Priority claim number 60 / 208,632 (32) Priority date June 1, 2000 (June 1, 2000) (33) Priority claiming country United States (US) (31) Priority claim number 60 / 231,906 (32) Priority date September 11, 2000 ( September 11, 2000 (33) Priority claiming country United States (US) (81) Designated country EP (AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR, IE, IT , LU, MC, NL, PT, SE, TR), OA (BF, BJ, CF, CG, CI, CM, GA, GN, GW, ML, MR, NE, SN, TD, TG), AP (GH , GM, KE, LS, MW, MZ , SD, SL, SZ, TZ, UG, ZW), EA (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), AE, AG, AL, AM, AT, AU, AZ, BA , BB, BG, BR, BY, BZ, CA, CH, CN, CR, CU, CZ, DE, DK, DM, DZ, EE, ES, FI, GB, GD, GE, GH, GM, HR, HU, ID, IL, IN, IS, JP, KE, KG, KP, KR, KZ, LC, LK, LR, LS, LT, LU, LV, MA, MD, MG, MK, MN, MW, MX , MZ, NO, NZ, PL, PT, RO, RU, SD, SE, SG, SI, SK, SL, TJ, TM, TR, TT, TZ, UA, UG, US, UZ, VN, YU, ZA, ZWF F terms (reference) 4C086 AA01 AA02 DA14 MA04 MA52 MA55 MA63 NA14 ZA66 ZA68 ZB11 4H006 AA03 A B28 UA12 UA13 UA42

Claims (27)

[Claims] 1. A method for treating inflammatory bowel disease, which comprises administering an effective amount of a vitamin D compound to a patient having the disease. 2. The method according to claim 1, wherein the disease is ulcerative colitis. 3. The method according to claim 1, wherein the disease is Crohn's disease. 4. The method according to claim 1, wherein the vitamin D compound is a 1α-hydroxy compound. 5. The method according to claim 4, wherein the vitamin D compound is 1α, 25-dihydroxyvitamin D ₃ . 6. The method according to claim 1, wherein the vitamin D compound is orally administered. 7. The method according to claim 1, wherein the vitamin D compound is parenterally administered. 8. The method of claim 1, wherein said vitamin D compound is administered transdermally. 9. The method according to claim 1, wherein the vitamin D compound is administered at a daily dose of 0.01 μg to 100 μg. 10. A method of treating inflammatory bowel disease, comprising an effective amount of the formula: [However, Y ₁ and Y ₂ in the formula are the same or different and are selected from the group consisting of hydrogen and hydroxy protecting groups, respectively; or both Z ₁ and Z ₂ is hydrogen, or Z ₁ and Z ₂ together is ═CH ₂ ; X ₁ and X ₂ are both hydrogen or one is hydrogen and the other is O-aryl, O-alkyl, alkyl, hydroxyalkyl or fluoroalkyl. , Α or β configuration, or taken together represent an alkylene group = CR ₆ R ₇ ; R ₆ and R ₇ are the same or different and each is hydrogen, alkyl, hydroxyalkyl. And fluoroalkyl, or taken together as a group-(
CH ₂ ) _x- ; x is an integer of 2 to 5 and may have an α or β configuration; the group R is of the formula: [Wherein the stereochemical center of the 20th carbon has the R or S configuration; Z is Y
, —OY, —CH ₂ OY, —C≡CY and —CH═CHY; the double bond may have a cis or trans geometry; and Y is hydrogen, methyl, —
COR ⁵ and structural formula: (In the formula, m and n each independently represent an integer of 0 to 5; R ¹ is hydrogen, deuterium, hydroxy, protected hydroxy, fluoro, trifluoromethyl, and linear or branched, and Selected from C _1-5 alkyl optionally having hydroxy or protected hydroxy substituents; R ² , R ³ and R ⁴ are each independently deuterium, deuterated alkyl, hydrogen, fluoro, tri Selected from fluoromethyl and C _1-5 alkyl which may be linear or branched and optionally bear hydroxy or protected hydroxy substituents; and R ¹ and R ² together oxo group or alkylidene (alkylidene) group,, = CR ² R ^3, or a group - (CH _{2) p} - are expressed; p is 2 to 5 integer; and, R ³ and R ⁴ together Oh Seo group or a group - (CH _{2) q} - are presented; q is 2 to 5 integer; and R ⁵ is hydrogen, hydroxy, protected hydroxy or C _1-5 alkyl; also the side chains 20, 22, or position 23 CH groups may be replaced by a nitrogen atom, or 20, 22 or 23-position of the group _{-CH, (CH 3) -,} - CH (R 3) -,
Or each of -CH (R ² )-may be replaced by an oxygen or sulfur atom respectively.]]] To a patient with the disease. A method characterized by. 11. The method of claim 10, wherein the disease is ulcerative colitis. 12. The method according to claim 10, wherein the disease is Crohn's disease. 13. The method of claim 10 wherein the compound is administered orally. 14. The method of claim 10, wherein the compound is administered parenterally. 15. The method of claim 10 wherein the compound is administered transdermally. 16. A daily dose of 0.01 μg to 100 of said compound.
The method according to claim 10, which is administered in μg. 17. The compound is 1,25-dihydroxyvitamin D ₃ , 1α-hydroxyvitamin D ₃ , 1,25-dihydroxyvitamin D ₂ , 19-nor-1,2.
5-dihydroxyvitamin D _2, 26,27- hexafluoro -1,25- dihydroxyvitamin D _2, 1,25- dihydroxy -24 (E) - dehydro-24-homo - vitamin D _3, 19-nor-1, 25-dihydroxy-21-epi-vitamin D ₃ , 1α, 25-dihydroxyvitamin D ₃ triacetic acid, and 25-acetyl-
The method according to claim 10, which is selected from the group consisting of 1α, 25-dihydroxyvitamin D ₃ . 18. The method of claim 10, wherein the patient is on a low calcium diet. 19. A method for preventing the progression of or delaying the onset of an inflammatory bowel disease in an individual susceptible to inflammatory bowel disease, which comprises administering to said individual an effective amount of a vitamin D compound. Method. 20. The vitamin D compound has the formula: [However, Y ₁ and Y ₂ in the formula are the same or different and are selected from the group consisting of hydrogen and hydroxy protecting groups, respectively; or both Z ₁ and Z ₂ is hydrogen, or Z ₁ and Z ₂ together is ═CH ₂ ; X ₁ and X ₂ are both hydrogen or one is hydrogen and the other is O-aryl, O-alkyl, alkyl, hydroxyalkyl or fluoroalkyl. , Α or β configurations, or taken together as an alkylidene
Group, = represents a CR ₆ R _7; R ₆ and R ₇ are the same or different and are either each hydrogen, alkyl, selected from hydroxyalkyl and fluoroalkyl, or together based on - (CH ₂ ) _x - represents a; x is an integer from 2 to 5, alpha
Or β configuration is possible; the group R has the formula: [Wherein the stereochemical center of the 20th carbon has the R or S configuration; Z is Y
, —OY, —CH ₂ OY, —C≡CY and —CH═CHY; the double bond may have a cis or trans geometry; and Y is hydrogen, methyl, —
COR ⁵ and structural formula: (In the formula, m and n each independently represent an integer of 0 to 5; R ¹ is hydrogen, deuterium, hydroxy, protected hydroxy, fluoro, trifluoromethyl, and linear or branched, and Selected from C _1-5 alkyl optionally having hydroxy or protected hydroxy substituents; R ² , R ³ and R ⁴ are each independently deuterium, deuterated alkyl, hydrogen, fluoro, tri Selected from fluoromethyl and C _1-5 alkyl which may be linear or branched and optionally bear hydroxy or protected hydroxy substituents; and R ¹ and R ² together oxo group or alkylidene (alkylidene) group,, = CR ² R ^3, or a group - (CH _{2) p} - are expressed; p is 2 to 5 integer; and, R ³ and R ⁴ together Oh Seo group or a group - (CH _{2) q} - are presented; q is 2 to 5 integer; and R ⁵ is hydrogen, hydroxy, protected hydroxy or C _1-5 alkyl; also the side chains 20, 22, or position 23 CH groups may be replaced by a nitrogen atom, or 20, 22 or 23-position of the group _{-CH, (CH 3) -,} - CH (R 3) -,
Or each of —CH (R ² ) — may be replaced with an oxygen or sulfur atom).]]]. 21. The method of claim 20, wherein said compound is 1α, 25-dihydroxyvitamin D ₃ . 22. The method of claim 20, wherein the compound is a 1α-hydroxy compound. 23. The compound is 1,25-dihydroxyvitamin D ₃ , 1α-hydroxyvitamin D ₃ , 1,25-dihydroxyvitamin D ₂ , 19-nor-1,2.
5-dihydroxyvitamin D _2, 26,27- hexafluoro -1,25- dihydroxyvitamin D _2, 1,25- dihydroxy -24 (E) - dehydro-24-homo - vitamin D _3, 19-nor-1, 25-dihydroxy-21-epi-vitamin D ₃ , 1α, 25-dihydroxyvitamin D ₃ triacetic acid, and 25-acetyl-
21. The method according to claim 20, which is selected from the group consisting of 1α, 25-dihydroxyvitamin D ₃ . 24. The method of claim 19, wherein said effective amount comprises from about 0.01 μg / day to about 100 μg / day of said compound. 25. The method of claim 19, wherein the compound is administered orally. 26. The method of claim 19, wherein the compound is administered parenterally. 27. The method of claim 19, wherein said compound is administered transdermally.