WO2006000923A2

WO2006000923A2 - Macrolide compositions as therapeutic agent

Info

Publication number: WO2006000923A2
Application number: PCT/IB2005/002899
Authority: WO
Inventors: Nicolas Fischer; Bernard Mach; Krzysztof Masternak; Tony Buss; Mui Mui Sim
Original assignee: Novimmune Sa; Merlion Pharmaceuticals Pte Ltd.
Priority date: 2004-06-03
Filing date: 2005-06-03
Publication date: 2006-01-05
Also published as: WO2006000923A3

Abstract

The present invention provides compositions including a macrolide compound that inhibits MHC class II expression. The compositions of the invention are used as an immunosuppressive agent in the treatment prior to, during and/or after organ or tissue transplantation, as well as in the treatment of immune-related disorders.

Description

MACROLIDE COMPOSITIONS AS THERAPEUTIC AGENT

Field of the Invention

This invention relates generally to methods of using compositions including a 12- membered ring macrolide compound as therapeutics in the treatment of immune-related disorders.

Background of the Invention

The immune system is highly complex and tightly regulated, with many alternative pathways capable of compensating deficiencies in other parts of the system. There are however occasions when the immune response becomes a cause of disease or other undesirable conditions if activated. Such diseases or undesirable conditions are, for example, autoimmune diseases, graft rejection after transplantation, allergy to innocuous antigens, psoriasis, chronic inflammatory diseases such as atherosclerosis, and inflammation in general. In these cases and others involving inappropriate or undesired immune response, there is a clinical need for immunosuppression. The pathways leading to these undesired immune responses are numerous and in many cases are not fully elucidated. However, they often involve a common step involving the activation of lymphocytes. Major Histocompatibility Complex molecules, encoded by the HLA gene cluster in man, are involved in many aspects of immunological recognition, including interaction between different lymphoid cells, as well as between lymphocytes and antigen-presenting cells. Major Histocompatibility Complex class II (MHC class II or MHC-II) molecules are directly involved in the activation of T lymphocytes and in the control of the immune response. MHC class II expression occurs on the surface of antigen-presenting cells (APCs). These cells are capable of presenting antigen to lymphocyte T-helpers, which control the development of an immune response. Thus, the expression of MHC class II molecules is the key to antigen presentation. Only a limited number of specialized cell types express MHC class II constitutively, numerous other cells become MHC class II positive upon stimulation. The stimulation is usually induction by a cytokine, particularly by interferon gamma (IFN-γ). Regulation of expression of MHC class II genes is highly complex and this tight control directly affects T lymphocyte activation and thus the control of the immune response. Accordingly, there exists a need for compositions that can be used in the treatment of immune-related diseases and/or disorders.

Summary of the Invention

The present invention provides compositions including a macrolide compound that inhibits MHC class II expression and that can be used as an immunosuppressive agent in the treatment prior to, during and/or after organ or tissue transplantation, as well as in the treatment of immune-related disorders. The macrolide compound of the invention includes a twelve membered ring. In one embodiment, the macrolide compound is a compound of the following formula ("formula 1") or pharmaceutically acceptable salts or hydrates thereof:

In formula (1), n represents an integer of 3 to 12; and R², R^3a, R^3b, R⁴, R^5a, R^6a, R^6b, R^7a, R^, R⁸, R^9a, R^9b, R¹⁰, R^na and R^nb are the same as or different from each other and each means (1) hydrogen, (2) hydroxy or (3) <1> methyl, <2> C_1-22 alkoxy, <3> ArCH₂O- (wherein Ar represents C_6-I4 aryl or 5-membered to 14-membered heteroaryl, each of which may have substituents), <4> C_2-22 acyloxy, <5> unsaturated C_3-22 acyloxy, <6> R⁰⁰COO- (wherein R^co represents C_6-I4 aryl, 5-membered to 14-membered heteroaryl, C_1-22 alkoxy, unsaturated C_2-22 alkoxy, C_6-14 aryloxy or 5-membered to 14-membered heteroaryloxy, each of which may have substituents), <7> Ci.₂₂alkylsulfonyloxy, <8> benzenesulfonyloxy or <9> R^slR^s2R^s3SiO. (wherein R^sl, R^s2 and R^s3 are the same as or different from each other and each represents methyl, ethyl, i-propyl, t-butyl or phenyl), each of which may have substituents, (4) halogen or (5) R^N1R^N2N-R^M- (wherein R^M represents a single bond or -CO- O-; and R^N1 and R^N2 are 1) the same as or different from each other and each represents <1> hydrogen or <2> (i) C_1-22 alkyl, (ii) unsaturated C_3-22 alkyl, (iii) C_2-22 acyl, (iv) unsaturated C₃. ₂₂ acyl, (v) C_6-14 aryl, (vi) 5-membered to 14-membered heteroaryl, (vii) benzyl., (viii) C_1-22 alkylsulfonyl or (ix) benzenesulfonyl, each of which may have substituents, or 2) -NR^N1R^N2 may be bonded together to represent 3-membered to 14-membered nitrogen-containing non- aromatic heterocyclic ring which may have substituents); further, R² may form a single bond

with either ofR^3a or R^3b to represent the partial structure: ; further, R^3a and R^3b may be bonded together to represent a ketone structure (=0) or an oxime structure {=NOR^0X (wherein R^ox represents C_1-22 alkyl, unsaturated C_3-22 alkyl, C_6-14 aryl, 5- membered to 14-membered heteroaryl or benzyl, each of which may have substituents)}; further, either of R^3a or R^3b and either of R^6a or R^6b may be bound together with oxygen to

represent the partial structure: ; further, R⁴ may form a single bond with

either of R^5a or R^5b and may represent the partial structure: further, R^5a and R^5b may be bonded together to represent a ketone structure (=0) or an oxime structure (=N0R^0X); further, R^6a and R^6b may be bonded together to represent a spirooxyrane ring or exomethylene; further, either of R^6a or R^6b and either of R^7a or R^7b may be bonded together to form a 1,3-dioxolane ring; further, R^7a and R^7b may be bonded together to represent a ketone structure (=0) or an oxime structure (=N0R^0X); further, R⁸ may form a single bond with - , J

either of R^9a or R^9b to represent the partial structure: further, R^9a and R^9b may be bonded together to represent a ketone structure (=0) or an oxime structure (=NOR^OX); further, two adjacent R^nas may form 0 to 3 ethylene structures where one R^naand one other R^na form a single bond; further, two R^nas may form 0 to 2 epoxy structures together with oxygen; further two R^nas may form one 2-oxo-l, 3-dioxane structure; further, R^na and R^nb on the same carbon may be bonded together to represent a ketone structure (=0) or an oxime structure (=NOR^OX), provided that (Restricted clause 1) when the above-mentioned compound is represented by the following formula (2):

at least one of R⁷ and R²¹ is hydroxy, acetoxy or methoxy; (Restricted clause 2) when the above-mentioned compound is represented by the following formula (3):

R⁷ is hydroxy or acetoxy; and R³, R⁶ and R²¹ are OH. In another embodiment, the macrolide compound is a compound of formula 4 or pharmaceutically acceptable salts or hydrates thereof:

(4) In another embodiment, the macrolide compound is a compound of formula 5 or a pharmaceutically acceptable salt or a hydrate thereof:

In formula (5), R², R¹⁰, R¹² and R¹⁴ are the same as or different from each other and each represents hydrogen or methyl; R^3a, R^3b, R^5a, R^5b, R^6a and R^6b are the same as or different from each other and each represents (1) hydrogen, (2) hydroxy, (3) <1> C_1-22 alkyl, <2> C_1-32 alkoxy, <3> ArCH₂O- (wherein Ar represents C_6-I4 aryl or 5-membered to 14- membered heteroaryl which may have substituents), <4> C_2-22 acyloxy, <5> unsaturated C_3-22 acyloxy, <6> -OCOR⁰⁰ (wherein R^co represents (i) C_6-I4 aryl, (ii) 5-membered to 14- membered heteroaryl, (iii) C_1-22 alkoxy, (iv) unsaturated C_2-22 alkoxy, (v) C_6-I4 aryloxy or (vi) 5-membered to 14-membered heteroaryloxy, each of which may have substituents), <7> Ci_-22 alkylsulfonyloxy, <8> benzenesulfonyloxy or <9> -OSiR^slR^s2R^s3 (wherein R^sl, R^s2 and R^s3 are the same as or different from each other and each represents methyl, ethyl, i-propyl, t-butyl or phenyl, (4) halogen, or (5) -R^M-NR^NIR^N2 (wherein R^M represents a single bond or -CO-O-; and R^N1 and R^N2 are 1) the same as or different from each other and each represents <1> hydrogen or <2> (i) Ci_-22 alkyl, (ii) unsaturated C_3-22 alkyl, (iii) C_2-22 acyl, (iv) unsaturated C_3-22 acyl, (v) C_6-I4 aryl, (vi) 5-membered to 14-membered heteroaryl, (vii) benzyl, (viii) Ci_-22 alkylsulfonyl or (ix) benzenesulfonyl, each of which may have substituents, or 2) NR^N1R^N2 may be bonded together to represent 3-membered to 14-membered nitrogen-containing non-aromatic heterocyclic ring which may have substituents); R^7a and R^7b are (1) different from each other and each represents 1) hydrogen, 2) -OR^H (wherein R^H is hydrogen, methyl or acetyl), 3) -OR^D (wherein R^D represents (i) C_1-22 alkyl (provided that when the alkyl is methyl, it is substituted), (ii) -CH₂Ar, (iii) C_3-22 acyl, (iv) unsaturated C_3-22 acyl, (v) -COR^CO, (vi) C_1-22 alkylsulfonyl, (vii) benzenesulfonyl. or (viii) -SiR^slR^s2R^s3) or 4) -R^M-NR^N1R^N2, or (2) R^7a and R^7b may be bonded together to represent <1> a ketone structure (=0) or represent an oxime structure (=NOR^OX; wherein R^ox represents <1> C_1-22 alkyl, <2> unsaturated C_3-22 alkyl, <3> C_6-14 aryl, <4> 5-membered to 14-membered heteroaryl or <5> benzyl, each of which may have substituents); further, R^3a and R^3b may be bonded together to represent a ketone structure (=0) or an oxime structure (=N0R^0X); further, R^6a or R^6b may be bonded together to represent a spirooxyrane ring or exomethylene; further, either of R^6a or R^6b and either of R^7a or R^7b may be bonded together to form a 1 ,3- dioxolane ring; G is represented by [G-I]

(wherein R^I6a and R^16b are the same as or different from each other and each represents hydrogen, methyl or hydroxy; R^17a, R^17b, R^18a, R^18b, R^19a, R^19b, R^20a, R^2Ob, R^21a and R^21b are the same as or different from each other and each represents (1) hydrogen, (2) methyl which may optionally be substituted, (3) -OR^H, (4) OR^D, (5) halogen or (6) -R^M-NR^N1R^N2 and

R^21C means (1) hydrogen or (2)

(wherein R^22a, R^22b and R^22c are the same as or different from each other and each represents <1> hydrogen, <2> methyl, <3> hydroxy, <4> • OR^H, <5> -OR^D, <6> -R^M-NR^N1R^N2 or <7> halogen.); further, either of R^18a or R^18b and either of R^19a or R^19b may form a single bond together to

represent the partial structure , or may be bonded with an oxygen

to represent the partial structure further, either of R^19a or R^19b and

either of R^20a or R^20b may form a single bond together to represent ; further, R^21a and R^21b may be bonded together to represent <1> a ketone structure (=0) or represent <2> an oxime structure (=NOR^OX); further, either of R or R and either of R or R may be bonded together to represent

the partial structure ; further, either of R or R and either of R^21a or R^21b may be bonded together to represent the partial structure G-II rø

; {wherein R^l6a, R^16b, R^17a, R^17b, R^l8a and R^18b have the same meanings as the definitions in formula (G-I); and R^18c represents

(1) hydrogen or (2) the formula (wherein R^βa, R^Gb, R^f4a and R^f4b are the same as or different from each other and each represents hydrogen, methyl, hydroxy, [3]

methoxy or acetoxy; and R represents methyl or ethyl)}; or G-II

{wherein R^16a, R^16b, R^17a and R^17b have the same meanings as the definitions in formula (G-I);

and R ,17c represents (1) hydrogen or (2) the formula (wherein R Sa , R^βb, R^f4a and R^f4b are the same as or different from each other and each represents hydrogen, methyl, hydroxy, methoxy or acetoxy; and R^β represents methyl or ethyl)}, provided that the restricted clauses 1 and 2 described above are included. In another embodiment, the macrolide compound is the compound of formula 6 or a pharmaceutically acceptable salt or hydrate thereof:

In formula (6), R², R^3a, R^3b, R^5a, R^5b, R^6a, R^6b, R^7a, R^7b, R¹⁰,R¹² and R¹⁴ have the same meanings as the definitions of the formula 5 (in the claim 2); R^12a and R¹³ (1) each represents hydrogen, or (2) are bound together to <1> form a

single bond and represent

or <2> form an epoxy and represent

R^{1 a} and R ⁵ (1) each represents hydrogen, or (2) are bound together to <1> form a

single bond and represent

or <2> form an epoxy and represent provided that (1) when R^I2a and R¹³ are bound together to form a single bond in formula (6), R^14a and R¹⁵ <1> are each hydrogen or <2> are bound together to form an epoxy; and (2) when R^14a and R¹⁵ are bound together to form a single bond, R^12a and R¹³ <1> are each hydrogen or <2> are bound together to form an epoxy; and G^sv (1) has the same meaning as the definition of G in formula 5, or (2) represents

(wherein — represents a single bond or a double bond; R^18a, R^18b, R^I9a and R^19b have the same meanings as the definitions in formula (5); R^19c is hydrogen or C^Malkyl). In another embodiment, the macrolide compound is the compound of formula 7 or a pharmaceutically acceptable salt or hydrate thereof:

In formula (7), R², R³, R^3b, R^6a, R^6b, R^7a, R^7b, R¹⁰, R¹², R¹⁴and G have the same meanings as the definitions in formula 5 of the claim 2; R^12a and R¹³ (1) each represents

hydrogen or (2) are bound together to <1> form a single bond and represent or

<2> form an epoxy and represent ; and R^I4a and R¹⁵ (1) each represents hydrogen

or (2) are bound together to <1> form a single bond and represent or <2>

form an epoxy and represent

In another embodiment, the macrolide compound is the compound of formula 8 or a pharmaceutically acceptable salt or hydrate thereof:

In formula (8), R², R^5a, R^5b, R^6a, R^6b, R^7a, R^7b, R¹⁰, R¹², R¹⁴ and G have the same meanings as the definitions in formula 5, as described above; and R^12a, R¹³, R^14a and R¹⁵ have the same meanings as the definitions in formula 7, as described above. In another embodiment, the macrolide compound is the compound of formula 9 or a pharmaceutically acceptable salt or hydrate thereof:

In formula (9), R², R^6a, R^7a, R^7b, R¹⁰, R¹², R¹⁴ and G have the same meanings as the definitions in formula 5, as described above; and R^12a, R¹³, R^14a and R¹⁵ have the same meanings as the definitions in formula 7, as described above. In another embodiment, the macrolide compound is the compound of formula 10 or a pharmaceutically acceptable salt or hydrate thereof:

In formula (10), R², R^3a, R^6a, R^6b, R¹⁰, R¹², R¹⁴ and G have the same meanings as the definitions in formula 5 (above); and R^12a, R¹³, R^14a and R¹⁵ have the same meanings as the definitions in formula 7 (above). In another embodiment, the macrolide compound is the compound of formula 11 or a pharmaceutically acceptable salt or hydrate thereof:

In formula (11), R¹², R^16a, R^I6b, R^17a, R^17b, R^2Oa, R^20b, R^21a, R^21b and R^21c have the same meanings as the definitions in formula 5 (above); R¹⁸ represents hydrogen or methyl; and G^m is represented by (GM-I)

(wherein R Λ2^Δ, τ R>3^Λa^a, τ R)3ⁱb⁰, τ R>5^Da^a, τ R>5^Db^D, τ R>6^oa^a, τ R>6⁰b^D, τ R>7^/a^a, τ R>7^/b^B and R¹⁰ have the same meanings as the definitions in formula 5 (above); (GM-II)

(wherein R², R^3a, R^3b, R^6a, R^6b, R^7a, R^7b and R¹⁰ have the same meanings as the definitions in formula 7) (GM-III)

(wherein R², R^5a, R^5b, R^6a, R^6b, R^7a, R^7b and R¹⁰ have the same meanings as the definitions in formula 8 described above) (GM-IV)

(wherein R², R^6a, R^7a, R^7b and R¹⁰ have the same meanings as the definitions in formula 9 described above) or (GM-V)

(wherein R , R , R , R and R have the same meanings as the definitions in formula 10 described), provided that the restricted clauses 1 and 2 described above are included. In another embodiment, the macrolide compound is the compound of formula 12 or a pharmaceutically acceptable salt or hydrate thereof:

In formula (12), R¹², R^16a, R^16b, R¹⁷, R^17a, R^17b, R¹⁷, R^20a, R^20b, R^21a, R^21b and R^21c have the same meanings as the definitions in formula 5; and R¹⁸ and G^m have the same meanings as the definitions in formula 11. In another embodiment, the macrolide compound is the compound of formula 13 or a pharmaceutically acceptable salt or hydrate thereof:

In formula (13), — represents a single bond or a double bond; R¹², R^16a, R^16b, R^17a, R^17b, R¹⁷, R^20a, R^20b, R^21a, R^21b and R^21c have the same meanings as the definitions in formula 5; and R¹⁸ and G^m have the same meanings as the definitions in formula 11. In another embodiment, the macrolide compound is the compound of formula 14 or a pharmaceutically acceptable salt or hydrate thereof:

In formula (14), R¹², R^16a, R^16b, R^17a, R^17b, R^18a, R^20a, R^20b, R^21a, and R^21c have the same meanings as the definitions in formula 5; and G^m has the same meaning as the definition in formula 11. In another embodiment, the macrolide compound is the compound of formula "H-I" or a pharmaceutically acceptable salt or hydrate thereof:

In the formula (H-I), R^2h, R^5h, R^6h, R^1Oh, R^12h, R^16h, R^20h, R^21h, and R^22h are the same as or different from each other and each represent (1) hydrogen, (2) methyl, (3) hydroxymethyl or (4) C^2'8 acyloxymethyl; R^3h>, R^5h>, R^6h>, R^7h>, R^16h>, R^17h' 'R^20h', R^21h>, and R^22h' are the same as or different from each other and each represents (1) hydrogen, (2) hydroxy, (3) methoxy or (4) C_2-8 acyloxy; R^5h and R^5h' may be bonded together to form a ketone structure (=0); R^21h and R^21h> may be bonded together to form a ketone structure (=0); and R^6h and R^6h may be bonded together to form a spirooxyrane structure, provided that the restricted clauses 1 and 2 described above are included. In some embodiments of the compound represented by the formula (H-I), the compound is selected from the group consisting of a compound in which R^2h is hydrogen, R^3h' is hydroxy, both of R^5h and R^5h' are hydrogen, R^6h is methyl, R^6h> is hydroxy, R^7h> is hydroxy, each of R^10h, R^12h and R^16his methyl, both of R^16h> and R^17h' are hydrogen, R^2Oh is methyl, R^20h' is hydrogen, R^21h> is hydroxy, both of R^21h and R^22h' are hydrogen and R^22h is methyl; a compound in which R^2h is hydrogen, R^3h hydroxy, both of R^5h and R^5h are hydrogen, R^6his methyl, R^6h> is hydroxy, R^7h' is acetoxy, each of R^1Oh, R^12h and R^16h is methyl, both of R^16h' and R^17h' are hydrogen, R^20h is methyl, R^20h' is hydrogen, R^21h' hydroxy, both of R^21h and R^22h> are hydrogen, and R^22h is methyl; a compound in which R^2h is hydrogen, R^3h' is hydroxy, both of R^5h and R^5h> are hydrogen, R^6h is methyl, R^6h> is hydroxy, R^7h> is acetoxy, each of R^1Oh, R^12h and R^16h is methyl, both of R^16h> and R^17h' are hydrogen, R^20h is methyl, R^20h' is hydrogen, both of R^21h and R^21h are bound together to form a ketone structure, R^22h is hydrogen and R^22h is methyl; a compound in which R^2h is hydrogen, R^3h is hydroxy, both of R^5h and R^5h are hydrogen, R^6h is methyl, R^6h' is hydroxy, R^7h' is acetoxy, each of R^1Oh, R^I2h and R^16h is methyl, R^16h> is hydroxy, R^17h> is hydrogen, R^20his methyl, R^20h> is hydrogen, R^21h' is hydroxy, both of R^21h and R^22h are hydrogen, and R^22h is methyl; a compound in which R^2h is hydrogen, R^3h is hydroxy, both of R^5h and R^5h are hydrogen, R^6h is methyl, R^6h> is hydroxy, R^7h is hydroxy, each of R^I0h, R^I2h and R^16h is methyl, R^16h> is hydroxy and R^17h> is hydrogen, R^20h is methyl, R^20h' is hydrogen, R^21h' is hydroxy, both of R^21h and R^22h> are hydrogen, and R^22h is methyl; a compound in which R^2h is hydrogen, R^3h> is hydroxy, both of R^5h and R^5h are hydrogen, R^6h is methyl, R^6h> is hydroxy, R^7h> is hydroxy, each of R^1Oh, R^12h and R^16h is methyl, both of R^16h> and R^17h> are hydrogen, R^20h is methyl, R^20h' is hydroxy, R^21h> is hydroxy, both of R^21h and R^22h' are hydrogen, and R^22h is methyl; a compound in which R^2h is hydrogen, R^3h is hydroxy, both of R^5h and R^5h are hydrogen, R^6h is methyl, R^6h> is hydroxy, R^7h> is propanoyloxy, each of R^10h, R^12h and R^16h is methyl, both of R^16h> and R^17h> are hydrogen, R^2Oh is methyl, R^20h> is hydrogen, R^21h> is hydroxy, both of R^21h and R^22h> are hydrogen, and R^22h is methyl; a compound in which R^2h is hydrogen, R^3h' is hydroxy, both of R^5h and R^5h> are hydrogen, R^6h is methyl, R^6h' is hydroxy, R^7h> is acetoxy, each of R^loh, R^12h and R^16h is methyl, both of R^16h> and R^17h> are hydrogen, R^20h is methyl, R^20h> is hydroxy, R^21h> is hydroxy, both of R^21h and R^22h> are hydrogen, and R^22h is methyl; a compound in which R^2h is hydrogen, R^3h> is hydroxy, both of R^5h and R^5h' are hydrogen, R^6h is methyl, R^6h> is hydroxy, R^7h> is acetoxy, each of R^10h, R^12h and R^16h is methyl, both of R^16h> and R^17h> are hydrogen, R^20h is methyl, R^20h> is hydrogen, R^21h> is hydroxy, and each of R^21h, R^22h> and R^22h is hydrogen; a compound in which R^2h is hydrogen, R^3h is hydroxy, R^5h is hydrogen, R^5h is hydroxy, R^6h is methyl, R^6h> is hydroxy, R^7h> is acetoxy, each of R^loh, R^12h and R^16h is methyl, both of R^16h> and R^17h' are hydrogen, R^20h is methyl, R^20h' is hydroxy, R^21h> is hydroxy, both of R^21h and R^22h' are hydrogen, and R^22h is methyl; a compound in which R^2h is hydrogen, R^3h> is hydroxy, R^5h is hydrogen , R^5h> is acetoxy, R^6h is methyl, R^6h> is hydroxy, R^7h> is acetoxy, each of R^1Oh, R^12h and R^16h is methyl, both of R^16h' and R^17h' are hydrogen, R^20h is methyl, R^2Oh> is hydrogen, R^21h> is hydroxy, both of R^21h and R^22h> are hydrogen, and R^22h is methyl; a compound in which R^2h is hydrogen, R^3h is acetoxy, both of R^5h and R^5h are hydrogen, R^6h is methyl, R^6h> is hydroxy, R^7h' is acetoxy, each of R^10h, R^12h and R^16h is methyl, both of R^16h' and R^17h> are hydrogen, R^20h is methyl, R^20h> is hydrogen, R^21h> is hydroxy, both of R^21h and R^22h> are hydrogen, and R^22h is methyl; a compound in which R^2h is hydrogen, R^3h' is hydroxy, both of R^5h and R^5h are hydrogen, R^6h is acetoxymethyl, R^6h> is hydroxy, R^7h> is acetoxy, each of R^1Oh, R^12h and R^16h is methyl, both of R^16h' and R^17h> are hydrogen, R^20h is methyl, R^20h> is hydrogen, R^21h> is hydroxy, both of R^21h and R^22h> are hydrogen, and R^22h is methyl; a compound in which R^2h is hydrogen, R^3h is hydroxy, both of R^5h and R^5h> are hydrogen, R^6h is methyl, R^6h> is hydroxy, R^7h> is acetoxy, each of R^1Oh, R^12h and R^16h is methyl, R^16h> is hydrogen, R^17h> are hydroxy, R^20h is methyl, R^20h> is hydrogen, R^21h> is hydroxy, both of R^21h and R^22h> are hydrogen, and R^22h is methyl; a compound in which R^2h is hydrogen, R^3h is hydroxy, both of R^5h and R^5h are hydrogen, R^6h is methyl, R^6h' is hydroxy, R^7h' is acetoxy, each of R^10h, R^12h and R^16h is methyl, both of R^16h> and R^17h> are hydrogen, both of R^20h and R^2Oh> is hydroxy, R^20h> are hydrogen, R^21h> is hydroxy, both of R^21h and R^22h> are hydrogen, and R^22h is methyl; a compound in which R^2h is hydrogen, R^3h is hydroxy, both of R^5h and R^5h are hydrogen, R^6h is methyl, R^6h> is hydroxy, R^7h> is acetoxy, both of R^1Oh and R^12h are methyl, each of R^16h, R^16h> and R^17h' is hydrogen, R^20h is methyl, R^20h' is hydrogen, R^21h> is hydroxy, both of R^21h and R^22h> are hydrogen, and R^22h is methyl; a compound in which R^2h is hydrogen, R^3h is hydroxy, both of R^5h and R^5h> are hydrogen, R^6h is methyl, R^6h' is hydroxy, R^7h> is acetoxy, both of R^loh and R^12h are methyl, each of R^12h, R^16h' and R^17h> is hydrogen, R^20h is methyl, R^20h' is hydrogen, R^21h> is hydroxy, both of R^21h and R^22h' are hydrogen, and R^22h is methyl; a compound in which R^2h is hydrogen, R^3h is hydroxy, both of R^5h and R^5h are hydrogen, R^6h is methyl, R^6h' is hydroxy, R^7h' is acetoxy, both of R^12h and R^16h are methyl, each of R^1Oh, R^16h> and R^17h> is hydrogen, R^20h is methyl, R^20h> is hydrogen, R^21h' is hydroxy, both of R^21h and R^22h' are hydrogen, and R^22h is methyl; a compound in which R^2h is hydrogen, R^3h is hydroxy, both of R^5h and R^5h are hydrogen, R^6h is acetoxymethyl, R^6h> is hydroxy, R^7h> is hydroxy, each of R^10h , R^12h, and R^16h is methyl, both of R^16h> and R^17h> are hydrogen, R^20h is methyl, R^20h' is hydrogen, R^21h> is hydroxy, both of R^21h and R^22h> are hydrogen, and R^22h is methyl; a compound in which R^2h is hydrogen, R^3h is hydroxy, both of R^5h and R^5h are hydrogen, R^6h is methyl, R^6h> is hydroxy, R^7h' is hydroxy, each of R^loh R^12h and R^16h is methyl, both of R^16hand R^17h' are hydrogen, R^20h is methyl, R^2Oh' is hydrogen, R^21h and R^21h> are bound together to form a ketone structure, R^22h> is hydrogen, and R^22h is methyl; a compound in which R^2h is hydrogen, R^3h> is hydroxy, each of R^5h, R^5h> and R^6h is hydrogen, R^6h> is acetoxy, R^7h> is hydroxy, each of R^loh, R^12h and R^16h is methyl, both of R^16h' and R^17' are hydrogen, R^20h is methyl, R^20h is hydrogen, R^21h> is hydroxy, both of R^21h' and R^22h' are hydrogen, and R^22h is methyl; a compound in which R^2h is methyl, R^3h> is hydroxy, both of R^5h and R^5h are hydrogen, R^6h is methyl, R^6h> is hydroxy, R^7h> is hydroxy, each of R^10h, R^12h and R^16h is methyl, both of R^16h and R^17h' are hydrogen, R^20h is methyl, R^20h> is hydrogen, R^21h' is hydroxy, both of R^21h and R^22h> are hydrogen, and R^22h is methyl; a compound in which R^2h is methyl, R^3h is hydroxy, both of R^5h and R^5h are hydrogen, R^6h is methyl, R^6h> is hydroxy, ^R7h> is acetoxy, each of R^10h, R^12h and R¹⁶¹Ms methyl, both of R^16h' and R^17h> are hydrogen, R^20h is methyl, R^20h> is hydrogen, R^21h> is hydroxy, both of R^21h and R^22h> are hydrogen, and R^22h is methyl; a compound in which R^2h is hydrogen, R^3h is hydroxy, R^5h is hydrogen, R^5h is hydroxy, R^6h is methyl, R^6h> is hydrogen, R^7h> is acetoxy, each of R^10h, R^12h and R^16h> is methyl, both of R^16h> and R^17h> are hydrogen, R^20h is methyl, R^20h' is hydrogen, R²"^1' is hydroxy, both of R^21h and R^22h> are hydrogen, and R^22h is methyl; a compound in which R^2h is hydrogen, R^3h> is hydroxy, each of R^5h, R^5Il> R^6h and R^6h> is hydrogen, R^7h' is hydroxy, each of R^IOh, R^12h and R^16his methyl, both of R^16h> and R^17h> are hydrogen, R^20h is methyl, R^20h> is hydrogen, R^21h> is hydroxy, both of R^21h and R^22h> are hydrogen, and R^22h is methyl; a compound in which R^2h is hydrogen, R^3h is hydroxy, both of R^5h and R^5h are hydrogen, R^6h and R^6h are bound together to form a spirooxyrane structure, R^7h is acetoxy, each of R^10h, R^12h and R^16h is methyl, both of R^21h and R^22h' are hydrogen, R^20h is methyl, R^20h' is hydrogen, R^21h' is hydroxy, both of R^21h and R^22h' are hydrogen, and R^22h is methyl; a compound in which R^2h is hydrogen, R^3h> is hydroxy, both of R^5h and R^5h' are hydrogen, R^6h and R^6h are bound together to form a spirooxyrane structure, R^7h is hydroxy, each of R^10h, R^12h and R^16h is methyl, both of R^16h> and R¹⁷'^1' are hydrogen, R^20h is methyl, R^20h' is hydrogen, R^21h' is hydroxy, both of R^21h and R^22h' are hydrogen, and R^22h is methyl; a compound in which R^2h is hydrogen, R^3h is hydroxy, both of R^5h and R^5h are hydrogen, R^6h is methyl, R^6h> is acetoxy, R^7h' is acetoxy, each of R^10h, R^12h and R^16h is methyl, both of R^16h' and R^17h' are hydrogen, R^20h is methyl, R^20h' is hydrogen, R^21h> is hydroxy, both of R^21h and R^22h' are hydrogen, and R^22h is methyl; a compound in which R^2h is hydrogen, R^3h is hydroxy, both of R^5h and R^5h are hydrogen, R^6h is methyl, R^6h> is hydroxy, R^7h> is acetoxy, each of R^1Oh, R^12h and R^16h is methyl, R^16h' is hydroxyl, R^I7h> is hydrogen, R^20h is methyl, R^20h' is hydrogen, R^21h and R^21h' are bound together to form a ketone structure, R^22h is hydrogen, and R^22h is methyl; a compound in which R^2h is hydrogen, R^3h is hydroxy, both of R^5h and R^5h are hydrogen, R^6h is methyl, R^6h' is hydroxy, R^7h' is acetoxy, each of R^1Oh, R^12h and R^16h is methyl, both of R^16h> and R^17h> are hydrogen, R^20h is methyl, R^20h> is hydrogen, R^21h is hydrogen, both of R^21h> and R^22h' are hydroxy, and R^22h is methyl; a compound in which R^2h is hydrogen, R^3h is hydroxy, R^5h is hydrogen, R^5h is hydroxy, R^6h methyl, R^6h> is hydroxy, R^7h' is acetoxy, each of R^1Oh, R^12h and R^16h is methyl, both of R^16h and R^17h' are hydrogen, R^20h is methyl, R^20h> is hydrogen, R^21h is hydrogen, both of R^21h> and R^22h> are hydroxy, and R^22h is methyl; a compound in which R^2h is hydrogen, R^3h' is hydroxy, both R^5h and R^5h' are hydrogen, R^6h is methyl, R^6h' is hydroxy, R^7h' is hydroxy, both of R^1Oh and R^16h are methyl, each of R^12h, R^16h> and R^17h> is hydrogen, R^20h is methyl, R^20h> is hydrogen, R^21h> is hydroxy, both of R^21h and R^22h' are hydrogen, and R^22h is methyl; and a compound in which R^2h is hydrogen, R^3h is hydroxy, both of R^5h and R^5h are bound together to form a ketone structure, R^6h is methyl, R^6h is hydroxy, R^7h is acetoxy, each of R^1Oh, R^12h and R^16h is methyl, both of R^16h> and R^17h' are hydrogen, R^20h is methyl, R^20h' is hydrogen, R^21h' is hydroxy, both of R^21h and R^22h' are hydrogen, and R^22h is methyl. In another embodiment, the macrolide compound is the compound of formula "H-II" or a pharmaceutically acceptable salt or hydrate thereof:

In the formula (H-II), R^2h, R^6h, R^10h, R^16h, R^20h, R^21h, R^22h and are the same as or different from each other and each represents (1) hydrogen, (2) methyl, (3) hydroxymethyl or (4) C_2-8 acyloxymethyl; R^3h', R^6h>, R^7h>, R^16h', R^17h>, R^20h>, R^21h> and R^22h' are the same as or different from each other and each represents (1) hydrogen, (2) hydroxy, (3) methoxy or (4) C_2-8 acyloxy; further, R^21h and R^21h' may be bonded together to form a ketone structure (=0); and further, R^6h and R^6h may be bonded together to form a spirooxyrane structure. In some embodiments of a macrolide compound of formula H-II, the compound is selected from the group consisting of a compound in which R^2h is hydrogen, R^3h> is hydroxy, R^6h is methyl, R^6h> is hydroxy, R^7h' is acetoxy, each of R_{1 O}h, R^12h and R^16h is methyl, both of R^16h> and R^17h', are hydrogen, R^20h methyl, R^20h> is hydrogen, R^21h> is hydroxy, both of R^21h and R^21h are hydrogen and R^22h is methyl; a compound in which R is hydrogen, R is hydroxy, R is methyl, R is hydroxy, R^7h> is hydroxy, each of R^1Oh, R^12h and R^16h is methyl, both of R^16h> and R^17h> are hydrogen, R^2Oh is methyl, R^20h> is hydrogen, R^21h> is hydroxy, both of R^21h and R^21h' are hydrogen, and R^22h is methyl; a compound in which R^2h is hydrogen. R^3h> is hydroxy, R^6h is methyl, R^6h> is hydroxy, R^7h> is acetoxy, each of R^1Oh, R^12h and R^16h is methyl, both of R^16h' and R^17h' are hydrogen, R^20h is methyl, R^20h> is hydrogen, R^21h and R^21h' form a ketone structure, R^22h> is hydrogen, and R^22h is methyl; a compound in which R^2h is hydrogen, R^3h is hydroxy, R^6h and R^6h are bound together to form a spirooxyrane structure, R^7h is acetoxy, each of R^10h, R^12h and R^16h is methyl, both of R^16h' and R^17h> are hydrogen, R^20h is methyl, R^2Oh> is hydrogen, R^21h> is hydroxy, both of R^21h and R^22h> are hydrogen, and R^22h is methyl; a compound in which R^2h is hydrogen. R^3h is hydroxy, R^6h is methyl, R^6h is acetoxy, R^7h> is acetoxy, each of R^1Oh, R^12h and R^16h is methyl, both of R^16h> and R^17h' are hydrogen, R^20h is methyl, R^20h' is hydrogen, R^21h> is hydroxy, both of R^21h and R^22h> are hydrogen, and R^22h is methyl; and a compound in which R^2h is hydrogen, R^3h is hydroxy, R^6h is methyl, R^6h is hydroxy, R^7h> is acetoxy, each of R^10h, R^12h and R^16h is methyl, R^16h' is hydrogen, R^17h' is hydroxy, R^20h is methyl, R^20h> is hydrogen, R^21h' is hydroxy, both of R^21h and R^22h' are hydrogen, and R^22h is methyl. In another embodiment, the macrolide compound is the compound of formula "H-III" or a pharmaceutically acceptable salt or hydrate thereof:

In the formula, R^2h, R^5h, R^6h, R^10h, R^12h, R^16h, R^20h, R^21h and R^22h are the same as or different from each other and each represents (1) hydrogen, (2) methyl, (3) hydroxymethyl or (4) C_2-8 acyloxymethyl; R^5h', R^6h', R^7h>, R^16h>, R^17h>, R^20h>, R^21h> and R^22h> are the same as or different from each other and each represents (1) hydrogen, (2) hydroxy, (3) methoxy or (4) C_2-8 acyloxy; further, R^5h and R^Sh> may be bonded together to form a ketone structure (=0); further, R^21h and R^21h may be bonded together to form a ketone structure (=0); further, R^6h and R^6h> may be bonded together to form a spirooxyrane structure. In some embodiments of a compound of formula H-III, the macrolide is selected from the group consisting of a compound in which R^2h is hydrogen, both of R^5h and R^5h are hydrogen, R^6h is methyl, R^6h> is hydroxy, R^7h> is hydroxy, each of R^1Oh, R^12h and R^16h is methyl, both of R^16h> and R^17h> are hydrogen, R^2Oh is methyl, R^20h' is hydrogen, R^21h> is hydroxy, both of R^21h and R^22h' are hydrogen and R^22h is methyl; a compound in which R^2h is hydrogen, both of R^5h and R^5h are hydrogen, R^6h is methyl, R^6h> is hydroxy, R^7h> is acetoxy, each of R^10h, R^12h and R^16h is methyl, both of R^16h' and R^17h> are hydrogen, R^20h is methyl, R^20h> is hydrogen, R^21h' is acetoxy, both of R^21h and R^22h> are hydrogen and R^22h is methyl; and a compound in which R^2h is hydrogen, both of R^5h and R^5h are hydrogen, R^6h is methyl, R^6h> is hydroxy, R^7h' is acetoxy, each of R^10h, R^12h and R^16h is methyl, both of R^16h' and R^17h' are hydrogen, R^20h is methyl, R^20h' is hydrogen, R^21h> is hydroxy, both of R^21h and R^22h' are hydrogen and R^22h is methyl. In another embodiment, the macrolide compound is the compound of formula "H-IV" or a pharmaceutically acceptable salt or hydrate thereof:

In the formula, R^2h, R^3h, R^4h, R^5h, R^6h, R^7h, R^10h, R^12h, R^16h, R^20h, R^21h and R^22h are the same as or different from each other and each represents (1) hydrogen, (2) methyl, (3) hydroxymethyl or (4) C_2-8 acyloxymethyl; R^3h>, R^5h>, R^6h', R^7h', R^16h>, R^17h>, R^20h>, R^21h> and R^22h> are the same as or different from each other and each represents (5) hydrogen, (6) hydroxy, (7) methoxy or (8) C_2-8 acyloxy; further, R^3h and R^3h may be bonded together to form a ketone structure (=0); further, R^5h and R^5h may be bonded together to form a ketone structure (=0); further, R^7h and R^7h may be bonded together to form a ketone structure (=0); R^21h and R^21h may be bonded together to form a ketone structure (=0); further,

R^4h and R^5h may form a single bond to represent ; and further, R^6h and R^6h may be bonded together to form a spirooxyrane structure, provided that the restricted clauses 1 and 2 described above are included. In some embodiments of a compound according to formula H-IV, the macrolide compound is selected from the group consisting of a compound in which R^2h is hydrogen, R^3h and R^3h are bound together to form a ketone structure, R^4h and R^5h form a single bond to

represent , R^5h' is hydrogen, R^6h is methyl, R^6h> is hydroxy, R^7h is hydrogen, R^7h' is acetoxy, each of R^1Oh, R^12h and R^16h is methyl, both of R^16h> and R^17h> are hydrogen, R^20h is methyl, R^20h' is hydrogen, R^21h' is hydroxy, both of R^21h and R^22h are hydrogen, and R^22h is methyl; and a compound in which R^2h is hydrogen, R^3h is hydrogen, R^3h> is hydroxy, each of R^4h, R^5h and R^5h> is hydrogen, R^6h is methyl, R^6h> is hydroxy, R^7h and R^7h' are bound together to form a ketone structure, each of R^1Oh, R^12h and R^16h is methyl, both of R^16h> and R^17h> are hydrogen, R^20h is methyl, R^20h> is hydrogen, R^21h> is hydroxy, both of R^21h and R^22h> are hydrogen, and R^22h is methyl. In another embodiment, the macrolide compound is the compound of formula "H-V" or a pharmaceutically acceptable salt or hydrate thereof:

In the formula (H-V), R^12h, R^16h, R^16h', R^17h', R^2Oh, R^20h> and R^21h> have the same meanings as the definitions in formula (H-I) described above; R^18h represents hydrogen or methyl; R^21h represents hydrogen, methyl or ethyl; and G^mh is represented by the formula (MH-I):

(wherein R^2h, R^3h>, R^5h, R^5h', R^6h, R^6h>, R^7h>, and R^1Oh have the same meanings as the definitions in formula (H-I)), the formula (MH-II):

(wherein R , R ^h , R , R^6h , R and R^1Oh have the same meanings as the definitions in formula (H-II) described above), the formula (MH-III):

(wherein R ,2^Mh, τ R>5^shⁿ, _π R5^Dhⁿ' , τ R»6^ohⁿ, τ R»6^ohⁿ' , τ R>7^/h^n! and R 1ⁱO^υh^{n ■} have the same meanings as the definitions in formula (H-III) described above), the formula (MH-IV):

(wherein R^2h, R^6h, R^7h and R^1Oh have the same meanings as the definitions in the formula (H-I)), or

(wherein R , R^3h , R , R^6h and R^1Oh have the same meanings as the definitions in formula (H-I)), provided that the restricted clauses land 2 described above are included. In some embodiments of the compound according to formula H-V, the compound is selected from the group consisting of a compound in which G^mh is represented by the formula (MH-I), R^2h is hydrogen, R^3h' is hydroxy, both of R^5h and R^5h' are hydrogen, R^6h is methyl, R^6h> is hydroxy, R^7h> is acetoxy, each of R^1Oh, R^12h and R^16h is methyl, each of R^16h>, R^17h' and R^I8h is hydrogen, each of R^20h, R^21h' and ™^h" is hydrogen and R^20h> is hydroxy; a compound in which G™¹¹ is represented by the formula (MH-I), R^2h is hydrogen, R^3h is hydroxyl, both of R^5h and R^5h' are hydrogen, R^6h is methyl, R^6h' is hydroxyl, R^7h' is acetoxy, each of R^1Oh, R^12h and R^16h is methyl, R^16h> is hydrogen, R^17h> is hydroxyl, and each of R^18h, R^2Oh, R^2Oh>, R^21h' and R^21h" is hydrogen; a compound in which G^mh is represented by the formula (MH-I), R^2h is hydrogen, R^3h is hydroxyl, both of R^5h and R^5h' are hydrogen, R^6h is methyl, R^6h> is hydroxyl, R^7h' is acetoxy, each of R^1Oh, R^12h and R^16h is methyl, R^16h' is hydrogen, R^17h> is hydroxyl, R^18h is methyl, and each of R^20h, R^20h>, R^21h> and R^21h" is hydrogen; a compound in which G^mh is represented by the formula (MH-I), R^2h is hydrogen, R^3h is hydroxy, both of R^5h and R^5h' are hydrogen, R^6h is methyl, R^6h> is hydroxy, R^7h' is acetoxy, each of R^1Oh, R^12h and R^16h is methyl, R^16h> is hydrogen, R^17h> is hydroxy, R^18h is methyl, and each of R^20h, R^20h>, R^21h> and R^21h" is hydrogen; a compound in which G^mh is represented by the formula (MH-V), R^2h is hydrogen, R^3h> is hydroxyl, R^6h is methyl, R^6h> is hydroxyl, each of R^1Oh, R^12h and R^16h is methyl, each of R^16h>, R^17h>, R^18h and R^20h' is hydrogen, R^20h is methyl, R^2Ih> is hydroxy, and R^21h" is ethyl. In another embodiment, the macrolide compound is the compound of formula "H-VI" or a pharmaceutically acceptable salt or hydrate thereof:

In the formula, R^12h, R^16h, R^16h>, R^17h>, R^20h, R^20h', R^21h, R^21h>, R^22h and R^22h' have the same meanings as the definitions in formula (H-I); G^mh has the same meaning as the definition in formula (H-V) described above. In some embodiments of the compound according to formula H-VI, the compound is selected from the group consisting of a compound in which G^mh is represented by the formula (MH-I), R^2h is hydrogen, R^3h' is hydroxy, both of R^5h and R^5h> are hydrogen, R^6h is methyl, R^6h' is hydroxy, R^7h> is acetoxy, each of R^1Oh, R^12h and R^16h is methyl, both of R^16h' and R^17h> are hydrogen, R^2Oh is methyl, both of R^20h' and R^21h are hydrogen, both of R^21h' and R^22h> are hydroxy, and R^22h is methyl; and a compound in which G¹"¹¹ is represented by the formula (MH-I), R^2h is hydrogen, R^3h is hydroxy, both of R^5h and R^5h' are hydrogen, R^6h is methyl, R^6h' is hydroxy, R^7h> is acetoxy, each of R^10h, R^12h and R^16h is methyl, both of R^16h' and R^17h> are hydrogen, R^20h is methyl, each of R^20h', R^21h and R^22h> is hydrogen, R^21h' is hydroxy, and R^22h is methyl. In another embodiment, the macrolide compound is the compound of formula "H- VII" or a pharmaceutically acceptable salt or hydrate thereof:

In the formula, G^mh has the same meaning as the definition in formula (H-V); — represents a single bond or a double bond; and R^12h, R^16h, R^16h', R^17h>, R^20h, R^20h>, R^21h, R^21h>, R^22h and R^22h have the same meanings as the definitions in formula (H-I). In some embodiments, the compound according to formula H-VII is selected from the group consisting of a compound in which G^mh is represented by the formula (MH-I), — represents a double bond, R is hydrogen, R is hydroxy, both of R and R are hydrogen, R^6h is methyl, R^6h> is hydroxy, R^7h> is acetoxy, each of R^10h, R^12h and R^16h is methyl, both of R^16h' and R^17h> are hydrogen, R^20h> is methyl, each of R^20h>, R^21h and R^22h> is hydrogen, R^21h> is hydroxy, and R^22h is methyl; and a compound in which G"* is represented by the formula (MH-I), — represents a single bond, R^2h is hydrogen, R^3h' is hydroxy, both of R^5h and R^5h> are hydrogen, R^6h is methyl, R^6h> is hydroxy, R^7h> is acetoxy, each of R^10h, R^12h and R^16h is methyl, both of R^16h> and R^17h> are hydrogen, R^2Oh is methyl, each of R^20h>, R^21h and R^22h> is hydrogen, R^21h> is hydroxy, and R^22h is methyl; and a compound in which G¹"¹¹ is represented by the formula (MH-II), — represents a double bond, R^2h is hydrogen, R^3h' is hydroxy, R^6h is methyl, R^6h> is hydroxy, R^7h> is acetoxy, each of R^1Oh, R^12h and R^16h is methyl, both of R^16h' and R^17h> are hydrogen, R^20h is methyl, each of R^20h>, R^21h and R^22h> is hydrogen, R^21h> is hydroxy, and R^22h is methyl. In another embodiment, the macrolide compound is the compound of formula "H- VIII" or a pharmaceutically acceptable salt or hydrate thereof:

In the formula, G^mh, R^12h, R^16h, R^16h', R^17h>, R^20h, R^22h and R^22h> have the same meanings as formula (H-I); and R represents hydrogen or hydroxy. In some embodiments, the macrolide compound according to formula H-VTII is selected from the group consisting of a compound in which G^mh is represented by the formula (MH-I), R^2h is hydrogen, R^3h' is hydroxy, both of R^5h and R^5h' are hydrogen, R^6h is methyl, R^6h> is hydroxy, R^7h> is acetoxy, each of R^10h, R^12h and R^16h is methyl, both of R^16h' and R^17h' are hydrogen, R^18h> is hydroxy, R^20h is methyl, R^22h' is hydroxy, and R^22h is methyl; and a compound in which G^mh is represented by the formula (MH-I), R^2h is hydrogen, R^3h> is hydroxy, both of R^5h and R^5h> are hydrogen, R^6h is methyl, R^6h> is hydroxy, R^7h' is acetoxy, each of R^1Oh, R^12h and R^16h is methyl, both of R^16h> and R^17h' are hydrogen, R^18h' is hydroxy, R^20h is methyl, R^22h> are hydrogen, and R^22h is methyl. In another embodiment, the macrolide compound is the compound of formula "H-IX" or a pharmaceutically acceptable salt or hydrate thereof:

In the formula, G^mh has the same meaning as the definition in formula (H-V); C^14"C¹⁵ and C^16~C¹⁷ are the same as or different from each other and each represents a single bond or a double bond; R^12h, R^16h and R^18h have the same meanings as the definition in formula (H-V); R^14h represents hydrogen or methyl; R^18h represents hydrogen or hydroxy; R^19h and R^19h are (1) the same as or different from each other and each represents hydrogen, methyl or hydroxy, or (2) R^19h and R^19h are bound together to represent a ketone structure (=0). In some embodiments, the macrolide compound according to formula H-IX is selected from the group consisting of a compound in which G^mh is represented by the formula (MR-I), C¹⁴-C¹⁵ is a double bond, C^1(bC¹⁷ is a single bond, R^2h is hydrogen, R^3h> hydroxy, both of R^5h and R^5h> are hydrogen, R^6h is methyl, R^6h' is hydroxy, R^7h> is acetoxy, each of R^loh, R^12h and R^16h is methyl, each of R^14h, R^18h and R^19h is hydrogen, and both of R^18h' and R^19h> are hydroxy; a compound in which G^mh is represented by the formula (MH-I),C^14~C¹⁵ is a single bond, C¹⁶-C¹⁷ is a double bond, R^2h is hydrogen, R^3h> is hydroxy, both of R^5h and R^5h> are hydrogen, R^6h is methyl, R^6h> is hydroxy, R^7h' is acetoxy, both of R^loh and R^14h are methyl, both of R^12h and R^16h are hydrogen, R^18h is methyl, R^18h> is hydroxy, and R^19h and R^19h' are bound together to form a ketone structure (=0); and a compound in which G^mh is represented by the formula (MH-I), C^14~C¹⁵ is a single bond, C¹⁶⁼C¹⁷ is a double bond, R^2h is hydrogen, R^3h' is hydroxy, both of R^5h and R^5h> are hydrogen, R^6h is methyl, R^6h> is hydroxy, R^7h> is acetoxy, both of R^loh and R^14h are methyl, both of R^12h and R^16h are hydrogen, R^18h is methyl, R^18h' is hydroxy, R^19h is hydrogen, and R^19h> is hydroxy. In another embodiment, the macrolide compound is the compound of formula "H-X" or a pharmaceutically acceptable salt or hydrate thereof:

In the formula, G^mh, R^16h and R^17h have the same meanings as the definitions in formula (H-V); R^14h represents hydrogen or methyl; C^14~C¹⁵ and C^16~C¹⁷ are the same as or different from each other and each represents a single bond or a double bond; R^18h' is hydrogen or hydroxy; and R^18h represents (1) methyl or (2) the formula (R-F). In some embodiments, the macrolide compound according to formula H-X is selected from the group consisting of a compound in which G^mh is represented by the formula (MH-I), R^18h" is represented by the formula (R-F), C¹⁴⁼C¹⁶ is a double bond, C^16"C¹⁷ is a single bond, R^2h is hydrogen, R^3h> is hydroxy, both of R^5h and R^5h> are hydrogen, R^6h is methyl, R^6h> is hydroxy, R^7h' is acetoxy, each of R^10h, R^12h and R^16h is methyl, both of R^14h and R^17h> are hydrogen, R^18h> is hydroxy, both of R^βa and R^β are methyl, both of R^Qb and R^f4b are hydrogen, and R^f4b is hydroxy; a compound in which G"* is represented by the formula (MH-I), C^14"C¹⁵ is a single bond, C^16"C¹⁷ is a double bond, R^2h is hydrogen, R^3h> is hydroxy, both of R^5h and R^5h> are hydrogen, R^6h is methyl, R^6h> is hydroxy, R^7h> is acetoxy, both of R^loh and R^14h are methyl, each of R^12h, R^16h and R^17h> is hydrogen, R^18h> is hydroxy, and R^18h" is methyl; and a compound in which Gmh is represented by the formula (MH-I), C^14"C¹⁵ is a double bond, C¹⁶-C¹⁷ is a single bond, R^2h is hydrogen, R^3h> is hydroxy, both of R^5h and R^5h> are hydrogen, R^6h is methyl, R^6h> is hydroxy, R^7h> is acetoxy, each of R^loh, R^12h and R^16h is methyl, both of R^14h and R^18h> are hydrogen, R^17h> is hydroxy, and R^18h" is methyl. In another embodiment, the macrolide compound is the compound of formula "H-XI" or a pharmaceutically acceptable salt or hydrate thereof:

In the formula, G^mh and R^12h have the same meanings as the definitions in formula (H-V); R^16h represents hydrogen, methyl or hydroxy; and R^17h represents (1) hydrogen or (2) the formula (R-F). In some embodiments, the macrolide compound according to formula H-XI is selected from the group consisting of a compound in which G^mh is represented by the formula (MH-I), R^17h" is represented by the formula (R-F), R^2h is hydrogen, R^3h' is hydroxy, both of R^5h and R^5h' are hydrogen, R^6h is methyl, R^6h> is hydroxy, R^7h' is acetoxy, each of R^1Oh, R^12h and R^16h" is methyl, both of R^βa and R^f4a are hydroxy, R^βb is hydrogen, R^f4b is methyl, and R^f5 is ethyl; and a compound in which G^mh is represented by the formula (MH-I), R^2h is hydrogen, R^3h> is hydroxy, each of R^5h, R^5h> and R^6h> is hydrogen, R^6h is methyl, R^7h' is acetoxy, both of R^loh and R^12h are methyl, R^16h" is hydroxy, and R^17h" is hydrogen. In another embodiment, the macrolide compound is the compound of formula 15 or a pharmaceutically acceptable salt or hydrate thereof:

In the formula (15), G^mr is represented by the formula (MD-I):

(wherein R^2r, R^3r', R^5r, R^5r>, R^6r, R^6r', R^7r> and R^1Or are the same as or different from each other and each represents 1) hydrogen, 2) methyl which may be substituted, 3) -OR^H (wherein R^H is <1> hydrogen, <2> methyl or <3> acetyl), 4) -OR^D (wherein R^D represents <1> Ci_-22 alkyl (provided that when the substituent is methyl, it is substituted), <2> -CH₂Ar, <3> C_3-22 acyl, <4> unsaturated C_3-22 acyl, <5> -COR^CO, <6> C_1-22 alkylsulfonyl, <7> benzenesulfonyl or <8> -SiR^slR^S2R^S3, each of which may be substituted) 5) halogen or 6) -R^M-NR^N1R^N2 (Ar, R^co, R^S1, R^S2, R^S3, R^M, R^N1 and R^N2 have the same meanings as the definitions of formula 5), further, R^5r and R^5r may be bonded together to represent a ketone structure; further, R^6r or R^6r may be bonded together to represent a spirooxyrane structure or an exo- methylene structure; further, either of R^6r or R^6r , and R^7r may be bonded together to represent a 1,3-dioxolane ring), the formula (MD-II):

(wherein R >2^zr^r, - Rr>3*r^r' , r R>6^or^r, τ R>6^or^r' , τ R>7^/r^r' and R^1Or have the same meanings as the above-mentioned definition), the formula (MD-III):

(wherein R^2r, R^5r, R^5r>, R^6r, R^6r', R^7r> and R^1Or have the same meanings as the above-mentioned definition), the formula (MD-IV):

(wherein R ^r, R ^r, R ^r , and R ^r have the same meanings as the above-mentioned definition), or the formula (MD-V):

(wherein R^2r, R^3r , R^6r, R^6r> and R^1Or have the same meanings as the above-mentioned definition); R^12r, R^16r, R^16f, R^17r', R^18r, R^20r, R^20r', R^21r, R^21r', R^22r and R^22r> are the same as or different from each other and each represents 1) hydrogen, 2) methyl which may be optionally substituted. 3) -OR^H (wherein R^H represents <1> hydrogen, <2> methyl or <3> acetyl), 4) -OR^D (wherein R^H represents <1> Ci_-22 alkyl (provided that when the substituent is methyl, it is substituted), <2> CH₂Ar, <3> C_3-22 acyl, <4> unsaturated C_3-22 acyl, <5> -COR^CO, <6> Ci_-22 alkylsulfonyl, <7> benzenesulfonyl, or <8> -SiR^slR^S2R^S3, each of which may be substituted), 5) halogen or 6) -R^M-NR^N1R^N2 (Ar, R^co, R^S1, R^S2, R^S3, R^M, R^N1 and R^N2 have the same meanings as the definitions in formula 5); further, R^21r and R^21r may be bonded together to represent <1> a ketone structure (=0) or an oxime structure (=NOR^OX: wherein R^ox has the same meaning as the definition in formula 5); when either one of A and B is 1) halogen, or 2) <1> alkylsulfonyloxy, <2> benzenesulfonyloxy or <3> C_1-22 alkoxy, each of which may have substituents, the other is 1) hydroxy, or 2) <1> Ci_-22 alkoxy or <2> C_2-22 acyloxy, each of which may have substituents. In another embodiment, the macrolide compound is the compound of formula 16 or a pharmaceutically acceptable salt or hydrate thereof:

In the formula (16) , R^3r>, R^5r, R^5r>, R^6r, R^6r>, R^H, R^17r', R^2Or, R^20r>, R^21r, R^21r", R^22r and R^22r> have the same meanings as the definitions in formula 15; and R^2s, R^1Os, R^12s, R^16s and R^18s are the same as or different from each other and each represents hydrogen or methyl. In another embodiment, the macrolide compound is the compound of formula 17 or a pharmaceutically acceptable salt or hydrate thereof:

In the formula (17) , R^3r', R^5r, R^5r>, R^6r, R^6r>, R^7r', R^17r>, R^20r, R^20r>, R^22r and R^22r' have the same meanings as the definitions in formula 15; and R^2s, R^1Os, R^16s, R^16s and R^18s have the same meanings as the definitions in formula 16. In another embodiment, the macrolide compound is the compound of formula 18 or a pharmaceutically acceptable salt or hydrate thereof:

In the formula (18), R , 17s ^s' represents hydrogen or hydroxy; R represents hydrogen or methyl; R ,21s' represents hydroxy or methoxy; and R AM represents -NR^¹R³"¹² (wherein R , a^! mi and R^am2 are (1) the same as or different from each other and each represents 1) hydrogen, or 2) <1> C_1-22 alkyl, <2> C_3-8 cycloalkyl, <3> unsaturated C_3-22 alkyl, <4> C_2-22 acyl, <5> unsaturated C_3-22 acyl, <6> C_6-M aryl, <7> C_3-8 cycloalkenyl, <8> 5-membered to 14- membered heteroaryl, <9> aralkyl, <10> heteroaralkyl, <11> Ci_-22 alkylsulfonyl, <12> benzenesulfonyl, <13> azetidin-2-yl, <14> pyrrolidin-3-yl, <15> piperazin-4-yl or <16>homopiperazin-4-yl, each of which may have substituents, or (2) -NR^amlR^am2 is bound together to represents an optionally substituted 3-membered to 14-membered nitrogen- containing non-aromatic heterocyclic ring). In some embodiments of the compound according to formula 18, the compound is selected from the group of compounds consisting of, (1) a compound in which R^ is represented by

, and further which may optionally have one to four substituents selected from hydroxy, amino, N-methylamino, N-ethylamino, N,N-dimethylamino, N₅N- diethylamino, N-ethyl-N-methylamino, azetidin-1-yl, pyrrolidin-1-yl, piperidin-1-yl, morpholin-1-yl, thiomorpholin-1-yl, piperazin-1-yl, 4-methylpiperazin-l-yl, 4-ethylpiperazin- 1-yl, N-(2-hydroxyethyl)amino, N-(3-hydroxypropyl) amino, N-(2-hydroxyethyl)-N- methylamino, N-(3-hydroxypropyl)-N-methylamino, N-(2-hydroxyethyl)-N-ethylamino or N- (3-hydroxypropyl)-N-ethylamino; (2) a compound in which R^M is represented by

and further, which may optionally have one to four of substituents selected from methyl, ethyl, n-propyl, hydroxy, hydroxymethyl, 2-hydroxyethyl and 3-hydroxypropyl; and (3) a compound in which R^ is represented by

, and further, which may optionally have one or two of substituents selected from methyl, ethyl, n-propyl, hydroxy, hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl, amino, N-methylamino, N-ethylamino, N,N-dimethylamino, N,N-diethylamino, N-ethyl-N-methylamino, azetidin- 1 -yl, pyrrolidin- 1 - yl, piperidin-1-yl, morpholin-1-yl and thiomorpholin-1-yl. In another embodiment, the macrolide compound is the compound of formula 19 or a pharmaceutically acceptable salt or hydrate thereof:

In the formula, G^mr and R , 12r ^r have the same meanings as the definitions in formula

(15); and Z represents oxygen or the formula:

(wherein R^z represents (1) hydrogen or (2) a and Ci_-8 alkyl, C^1"8 alkenyl or C^1"8 alkynyl which may have substituents and an epoxy structure). In another embodiment, the macrolide compound is the compound of formula 20 or a pharmaceutically acceptable salt or hydrate thereof:

In the formula (20), A' and B' are bound together with oxygen to represent an epoxy structure, or either one of them represents hydroxy and the other represents any one of chlorine, bromine, hydroxy and methoxy; R^21a and R^21b are bound together with oxygen to represent a ketone structure, or either one of them represents hydrogen and the other represents any one of hydroxy, methoxy and -OR¹"; R³ , R⁶ and R^7" are the same as or different from each other and each represents hydrogen, acetyl or -R^m; R¹⁶, R¹⁷ and R²⁰ are the same as or different from each other and each represents hydrogen, hydroxy or -OR^m; R¹² represents methyl, -CH₂OH or -CH₂OR"¹ (wherein R^m represents C_1-C₈ alkyl, C_2-C₈ acyl, R^bnCH₂, R^bnCO or R^nlRⁿ²NCO; R^bn represents C_6-C₁₀ aryl or C_5-C₁₄ heteroacyl. which may optionally have one or more substituents described below, R^nl and R"² are the same as or different from each other and each represents hydrogen, Cj-C₈ alkyl, C_3-C₇ cycloalkyl, benzyl which may optionally have one or more substituents described below, or R^nl and R"² are bound together to represent pyrrolidine, piperidine, piperazine, N-substituted piperazine or morpholine; The substituent described here indicates the following. a) C_1-C₈ alkyl, C_1-C₈ alkoxy, C_2-C₈ acyl, b) fluoro, chloro, bromo, iodo, c) carboxylic acid, sulfonic acid, carboxylic acid ester, carboxamide which may optionally have substituents on nitrogen, d) nitro, amino, N-monosubstituted amino, N, N-disubstituted amino, e) a hydroxy group, mercaptane, C_1-C₈ alkylthio, C_1-C₈ alkylsulfoxide, C_1-C₈ alkylsulfone, provided that the restricted clauses 1 and 2, described above, are included. In another embodiment, the macrolide compound is the compound of formula 21 or a pharmaceutically acceptable salt or hydrate thereof:

In the formula (21), R³ and R⁶ represent hydrogen; R⁷ represents hydrogen or acetyl; R¹⁶, R¹⁷ and R²⁰ are the same as or different from each other and each represents hydrogen or hydroxy; R^21a and R^21b are bound together with oxygen to represent a ketone structure, or either one of them represents hydroxy or methoxy and the other represents hydrogen; and R¹² represents methyl or -CH₂OH, provided that the restricted clauses 1 and 2, described above, are included. In one embodiment of a compound according to formula 21, R³ , R⁶ and R¹⁷ are hydrogen; R⁷ is hydrogen or acetyl; R¹⁶ and R²⁰ are the same as or different from each other and each represents hydrogen or hydroxy; R^21a and R^21b are bound together with oxygen, or either one of them represents hydroxy and the other is hydrogen; and R¹² is methyl. In another embodiment of a compound according to formula 21, R³ , R⁶ and R¹⁷ are hydrogen; R⁷ is acetyl; R¹⁶ and R¹⁷ are the same as or different from each other and each represents hydrogen or hydroxy; R^21a and R^21b are bound together with oxygen, or either one of them represents hydroxy and the other is hydrogen; and R¹² represents methyl or -CH₂OH. In yet another embodiment of the compound according to formula 21, R³ , R⁶ , R⁷ , R¹⁷, R²⁰ and R^21a are hydrogen; R¹⁶ and R^21b are hydroxy; and R¹² is methyl. In another embodiment of a compound according to formula 21, R³ , R⁶ , R⁷ , R¹⁶, R¹⁷ and R^21a are hydrogen; R²⁰ and R^21b are hydroxy; and R¹² is methyl. In other embodiments of the compound according to formula 21, R^3", R^6", R^7", R¹⁶, R¹⁷ and R^21a are hydrogen; R^21b is hydroxy; and R¹² is methyl. In another embodiment of a compound according to formula 21, R^3", R^6", R¹⁶, R¹⁷ and R^21a are hydrogen; R²⁰ and R^21b are hydroxy; R^7" is acetyl; and R¹² is methyl. In other embodiments of the compound according to formula 21, R^3", R^6", R¹⁷, R²⁰ and R^21a are hydrogen; R¹⁶ and R^21b are hydroxy; R⁷ is acetyl; and R¹² is methyl. In another embodiment of a compound according to formula 21, R³ , R^{6 '}, R¹⁶, R¹⁷ and R²⁰ are hydrogen; R^21a and R^21b are bound together with oxygen; R⁷ is acetyl; and R¹² is methyl. In yet another embodiment of a compound according to formula 21, R^3", R^6", R¹⁶, R¹⁷, R²⁰ and R^21a are hydrogen; R^21b is hydroxy; R^7" is acetyl; and R¹² is methyl. The macrolide compositions of the invention can be used to treat or alleviate a symptom associated with an immune-related disorder, such as, for example, autoimmune diseases and inflammatory disorders. Autoimmune diseases and inflammatory disorders that are treated using the macrolide compositions of the invention, include, for example, connective tissue diseases {e.g., systemic lupus erythematosus (SLE), rheumatoid arthritis, systemic sclerosis (scleroderma), Sjogren's syndrome), neuromuscular diseases {e.g., multiple sclerosis (MS), myasthenis gravis, Guillain-Barre syndrome), endocrine diseases {e.g., Hashimoto's thyroiditis, Graves' disease, insulin-dependent (Type 1) diabetes), gastrointestinal diseases {e.g., inflammatory bowel disease, Crohn's disease, ulcerative colitis), autoimmune skin diseases {e.g., psoriasis, psoriatic arthritis, other autoimmune diseases {e.g., vasculitis syndromes, hematologic autoimmune diseases, and uveitis), Alzheimer's disease, asthma, atopic allergy, allergy, atherosclerosis, bronchial asthma, eczema, glomerulonephritis, graft vs. host disease, hemolytic anemias , osteoarthritis, sepsis, stroke, vasculitis, diabetic retinopathy and ventilator induced lung injury. The macrolide compositions of the invention are used as immunosuppression agents following organ transplantation. The compositions include a pharmaceutically acceptable carrier and a macrolide compound, or pharmaceutically acceptable salts or hydrates thereof. For example, the compositions of the invention include a macrolide compound according to formulae 1-21 or HI-HXI. In one embodiment, the macrolide compositions used to treat an immune-related disorder are administered in combination with any of a variety of known anti-inflammatory and/or immunosuppressive compounds. Suitable anti-inflammatory and/or immunosuppressive compounds for use with the macrolide compounds of the invention include, but are not limited to, methotrexate, cyclosporin A (including, for example, cyclosporin microemulsion), tacrolimus, corticosteroids, statins, interferon beta, nonsteroidal anti-inflammatory drugs (NSAIDs) and the disease-modifying anti-rheumatic drugs (DMARDs). The macrolide compositions of the invention are also used as immunosuppression agents to treat a patient prior to, during and/or after organ or tissue transplantation (e.g. , skin transplant, kidney transplant, pancreatic islet transplant, cardiac transplant). These immunosuppressive macrolide compositions include a pharmaceutically acceptable carrier and a compound of formula 1-21 and HI-HXI, or pharmaceutically acceptable salts or hydrates thereof. In one embodiment, these immunosuppressive macrolide compositions are administered in combination with any of a variety of known anti-inflammatory and/or immunosuppressive compounds, such as, for example, methotrexate, cyclosporin A (including, for example, cyclosporin microemulsion), tacrolimus, corticosteroids and statins. The present invention also provides methods of treating or alleviating a symptom associated with an immune-related disorder or a symptom associated with organ or tissue transplantation rejection. The methods include administering to a patient a pharmaceutically acceptable carrier and a macrolide composition, or pharmaceutically acceptable salts or hydrates thereof. In a preferred embodiment, the macrolide compound is a compound of formula 1-21 and HI-HXI.

Detailed Description of the Invention

/ The present invention provides compositions that can be used in the treatment of immune-related disorders, as well as in the treatment prior to, during and/or after organ or tissue transplantation. The compositions of the invention include a compound that modulates and/or regulates an immune response. This compound is a macrolide compound. Macrolides are a group of antibiotics, produced for example by various strains of Streptomyces, that have a complex macrocyclic structure. These macrocyclic compounds are formed by chain extension and cyclized into a large, typically 12-, 14-, or 16- membered lactone. Often, macrolides are glycosylated. The macrolide compound of the invention includes a twelve membered ring and in one embodiment, the macrolide is a compound according to formula 1 or pharmaceutically acceptable salts or hydrates thereof:

In formula (1), n represents an integer of 3 to 12; and R², R , R , R⁴, R^5a, R^6a, R^6b, R^7a, R^7b, R⁸, R^9a, R^9b, R¹⁰, R^πa and R^nb are the same as or different from each other and each means (1) hydrogen, (2) hydroxy or (3) <1> methyl, <2> Ci_-22 alkoxy, <3> ArCH₂O- (wherein Ar represents C_6-I4 aryl or 5-membered to 14-membered heteroaryl, each of which may have substituents), <4> C_2-22 acyloxy, <5> unsaturated C_3-22 acyloxy, <6> R⁰⁰COO- (wherein R^co represents C_6-I4 aryl, 5-membered to 14-membered heteroaryl, Ci_-22 alkoxy, unsaturated C_22-2 alkoxy, C_6-I4 aryloxy or 5-membered to 14-membered heteroaryloxy, each of which may have substituents), <7> Ci_-22 alkylsulfonyloxy, <8> benzenesulfonyloxy or <9> R^slR^s2R^s3Si0_ (wherein R^sl, R^s2 and R^s3 are the same as or different from each other and each represents methyl, ethyl, i-propyl, t-butyl or phenyl), each of which may have substituents, (4) halogen or (5) R^N1R^N2N-R^M- (wherein R^M represents a single bond or -CO- O-; and R^N1 and R^N2 are 1) the same as or different from each other and each represents <1> hydrogen or <2> (i) Ci_-22 alkyl, (ii) unsaturated C_3-22 alkyl, (iii) C_2-22 acyl, (iv) unsaturated C_3- ₂₂ acyl, (v) C_6-I4 aryl, (vi) 5-membered to 14-membered heteroaryl, (vii) benzyl, (viii) C_1-22 alkylsulfonyl or (ix) benzenesulfonyl, each of which may have substituents, or 2) -NR^N1R^N2 may be bonded together to represent 3-membered to 14-membered nitrogen-containing non- aromatic heterocyclic ring which may have substituents); further, R² may form a single bond

with either of R^3a or R^3b to represent the partial structure: ; further, R^3a and R^3b may be bonded together to represent a ketone structure (=0) or an oxime structure {=N0R^0X (wherein R^ox represents Ci_-22 alkyl, unsaturated C_3-22 alkyl, C_6-14 aryl, 5- membered to 14-membered heteroaryl or benzyl, each of which may have substituents)}; further, either of R^3a or R^3b and either of R^6a or R^6b may be bound together with oxygen to

represent the partial structure: ; further, R⁴ may form a single bond with

either of R^5a or R^5b and may represent the partial structure: ; further, R^5a and R^5b may be bonded together to represent a ketone structure (=0) or an oxime structure (=NOR^OX); further, R^6a and R^6b may be bonded together to represent a spirooxyrane ring or exomethylene; further, either of R^6a or R^6b and either of R^7a or R^7b may be bonded together to form a 1,3-dioxolane ring; further, R^7a and R⁷¹³ may be bonded together to represent a ketone structure (=0) or an oxime structure (=NOR^OX); further, R⁸ may form a single bond with

either of R^9a or R^9b to represent the partial structure: ; further, R^9a and R^9b may be bonded together to represent a ketone structure (=0) or an oxime structure (=N0R^0X); further, two adjacent R^nas may form O to 3 ethylene structures where one R^na and one other R^na form a single bond; further, two R^nas may form O to 2 epoxy structures together with oxygen; further two R^nas may form one 2-oxo-l, 3-dioxane structure; further, R^na and R^nb on the same carbon may be bonded together to represent a ketone structure (=0) or an oxime structure (=N0R^0X), provided that (Restricted clause 1) when the above-mentioned compound is represented by the following formula (2):

at least one of R and R is hydroxy, acetoxy or methoxy; (Restricted clause 2) when the above-mentioned compound is represented by the following formula (3):

,

In formula (5), R², R¹⁰, R¹² and R¹⁴ are the same as or different from each other and each represents hydrogen or methyl; R^3a, R^3b, R^5a, R^5b, R^6a and R^6b are the same as or different from each other and each represents (1) hydrogen, (2) hydroxy, (3) <1> C_1-22 alkyl, <2> C_1-22 alkoxy, <3> ArCH₂O- (wherein Ar represents C_6-I4 aryl or 5-membered to 14- membered heteroaryl which may have substituents), <4> C_2-22 acyloxy, <5> unsaturated C_3-22 acyloxy, <6> -OCOR^CO (wherein R^co represents (i) C_6-14 aryl, (ii) 5-membered to 14- membered heteroaryl, (iii) C_1-22 alkoxy, (iv) unsaturated C_2-22 alkoxy, (v) C_6-I4 aryloxy or (vi) 5-membered to 14-membered heteroaryloxy, each of which may have substituents), <7> C_1-22 alkylsulfonyloxy, <8> benzenesulfonyloxy or <9> -OSiR^slR^s2R^s3 (wherein R^sl, R^s2 and R^s3 are the same as or different from each other and each represents methyl, ethyl, i-propyl, t-butyl or phenyl, (4) halogen or (5) -R^M-NR^N1R^N2 (wherein R^M represents a single bond or -CO-O-; and R^NI and R^N2 are 1) the same as or different from each other and each represents <1> hydrogen or <2> (i) C_1-22 alkyl, (ii) unsaturated C_3-22 alkyl, (iii) C_2-22 acyl, (iv) unsaturated C_3-22 acyl, (v) C_6-14 aryl, (vi) 5-membered to 14-membered heteroaryl, (vii) benzyl, (viii) Ci_-22 alkylsulfonyl or (ix) benzenesulfonyl, each of which may have substituents, or 2) NR^N1R^N2 may be bonded together to represent 3-membered to 14-membered nitrogen-containing non-aromatic heterocyclic ring which may have substituents); R^7a and R^7b are (1) different from each other and each represents 1) hydrogen, 2) -OR^H (wherein R^H is hydrogen, methyl or acetyl), 3) -OR^D (wherein R^D represents (i) Ci_-22 alkyl (provided that in case of methyl, it always has substituents), (ii) -CH₂Ar, (iii) C_3-22 acyl, (iv) unsaturated C_3-22 acyl, (v) -COR^CO, (vi) Ci_-22 alkylsulfonyl, (vii) benzenesulfonyl, or (viii) -SiR^slR^s2R^s3) or 4) -R^M-NR^N1R^N2, or (2) R^7A and R^7b may be bonded together to represent <1> a ketone structure (=0) or represent an oxime structure (=NOR^OX; wherein R^ox represents <1> Ci_-22 alkyl, <2> unsaturated C_3-22 alkyl, <3> C_6-I4 aryl, <4> 5-membered to 14-membered heteroaryl or <5> benzyl, each of which may have substituents); further, R^3a and R^3b may be bonded together to represent a ketone structure (=0) or an oxime structure (=NOR^OX); further, R^6a or R^6b may be bonded together to represent a spirooxyrane ring or exomethylene; further, either of R^6a or R^6b and either of R^7a or R^7b may be bonded together to form a 1,3- dioxolane ring; G is represented by [G-I]

(wherein R^16a and R^16b are the same as or different from each other and each represents hydrogen, methyl or hydroxy; R^17a, R^17b, R^18a, R^18b, R^19a, R^19b, R^20a, R^20b, R^21a and R^21b are the same as or different from each other and each represents (1) hydrogen, (2) methyl which may optionally have substituents, (3) -OR^H, (4) OR^D, (5) halogen or (6) -R^M-NR^N1R^N2 and

R^Z1C means (1) hydrogen or (2)

(wherein R"^a, R^" and R^Z2V are the same as or different from each other and each represents <1> hydrogen, <2> methyl, <3> hydroxy, <4> • OR^H, <5> -OR^D, <6> -R^M-NR^N1R^N2 or <7> halogen.); further, either of R^18a or R^18b and either of R^19a or R^19b may form a single bond together to

represent the partial structure , or may be bonded with an oxygen

to represent the partial structure ; further, either of R^19a or R^19b and

the partial structure

and either of R^21a or R^21b may be bonded together to represent the partial structure G-II m

; {wherein R^16a, R^16b, R^17a, R^17b, R^18a and R^18b have the same meanings as the definitions in formula (G-I); and R^18c represents

(1) hydrogen or (2) the formula (wherein R^βa, R^βb, R^f4a and R^f4b are the same as or different from each other and each represents hydrogen, methyl, hydroxy, methoxy or acetoxy; and R^β represents methyl or ethyl)}; or 13]

G-m

{wherein R^16a, R^16b, R^17a and R^17b have the same meanings as the definitions in formula (G-I); and R^17c represents (1) hydrogen or (2) the formula

(wherein R^βa, R^Gb, R^f4a and R^f4b are the same as or different from each other and each represents hydrogen, methyl, hydroxy, methoxy or acetoxy; and R^β represents methyl or ethyl)}, provided that the restricted clauses 1 and 2 described above are included. In another embodiment, the macrolide compound is the compound of formula 6 or a pharmaceutically acceptable salt or hydrate thereof:

single bond and represent

or <2> form an epoxy and represent

R^14a and R¹⁵ (1) each represents hydrogen, or (2) are bound together to <1> form a

single bond and represent ; provided that (1) when R^12a and R¹³ are bound together to form a single bond in formula (6), R^14a and R¹⁵ <1> are each hydrogen or <2> are bound together to form an epoxy; and (2) when R^14a and R¹⁵ are bound together to form a single bond, R^12a and R¹³ <1> are each hydrogen or <2> are bound together to form an epoxy; and G^sv (1) has the same meaning as the definition of G in formula 5, or (2) represents

(wherein — represents a single hond or a double bond; R^18a, R^18b, R^19a and R^19b have the same meanings as the definitions in formula (5); R^19c is hydrogen or C¹⁴alkyl). In another embodiment, the macrolide compound is the compound of formula 7 or a pharmaceutically acceptable salt or hydrate thereof:

In formula (7), R², R³, R^3b, R^6a, R^6b, R^7a, R^7b, R¹⁰, R¹². R¹⁴and G have the same meanings as the definitions in formula 5 of the claim 2; R^12a and R¹³ (1) each represents

hydrogen or (2) are bound together to <1> form a single bond and represent or

<2> form an epoxy and represent

and R^14a and R¹⁵ ( 1 ) each represents hydrogen

or (2) are bound together to <1> form a single bond and represent or <2>

form an epoxy and represent

In formula (9), R², R^6a, R^7a, R™, R¹⁰, R¹², R¹⁴ and G have the same meanings as the definitions in formula 5, as described above; and R^12a, R¹³, R^14a and R¹⁵ have the same meanings as the definitions in formula 7, as described above. In another embodiment, the macrolide compound is the compound of formula 10 or a pharmaceutically acceptable salt or hydrate thereof:

In formula (11), R¹², R^16a, R^16b, R^17a, R^17b, R^20a, R^20b, R^21a, R^21b and R^21c have the same meanings as the definitions in formula 5 (above); R¹⁸ represents hydrogen or methyl; and G^m is represented by (GM-I)

(wherein R², R^3a, R^3b, R^5a, R^5b, R^6a, R^6b, R^7a, R^7b and R¹⁰ have the same meanings as the definitions in formula 5 (above); (GM-II)

(wherein R², R^3a, R^3b, R^6a, R^6b, R^7a, R^7b and R¹⁰ have the same meanings as the definitions in formula 7); (GM-III)

(wherein R², R^5a, R^5b, R^6a, R^6b, R^7a, R^7b and R¹⁰ have the same meanings as the definitions in formula 8 described above); (GM-IV)

(wherein R², R^6a, R^7a, R^7b and R¹⁰ have the same meanings as the definitions in formula 9 described above), or (GM-V)

(wherein R², R^3a, R^6a, R^6b and R¹⁰ have the same meanings as the definitions in formula 10 described), provided that the restricted clauses 1 and 2 described above are included. In another embodiment, the macrolide compound is the compound of formula 12 or a pharmaceutically acceptable salt or hydrate thereof:

In formula (12), R¹², R^16a, R^16b, R¹⁷, R^17a, R^17b, R¹⁷, R^2Oa, R^20b, R^21a, R^21b and R^21c have the same meanings as the definitions in formula 5; and R¹⁸ and G^m have the same meanings as the definitions in formula 11. In another embodiment, the macrolide compound is the compound of formula 13 or a pharmaceutically acceptable salt or hydrate thereof:

In formula (13), — represents a single bond or a double bond; R¹², R^16a, R^16b, R^17a, R^17b, R¹⁷, R^20a, R^2Ob, R^21a, R^21b and R^21c have the same meanings as the definitions in formula 5; and R¹⁸ and G^m have the same meanings as the definitions in formula 11. In another embodiment, the macrolide compound is the compound of formula 14 or a pharmaceutically acceptable salt or hydrate thereof:

In the formula (H-I), R^2h, R^5h, R^6h, R^lo\ R^12h, R^16h, R^20h, R²¹\ and R^22h are the same as or different from each other and each represents: (1) hydrogen, (2) methyl, (3) hydroxymethyl or (4) C_2-8 acyloxymethyl; R^3h>, R^5h>, R^6h>, R^7h', R^16h>, R^17h> -R^2Oh', R^21h>, and R^22h> are the same as or different from each other and each represents: (1) hydrogen, (2) hydroxy, (3) methoxy, or (4) C_2-8 acyloxy; R^5h and R^5h> may be bonded together to form a ketone structure (=0); R^21h and R^21h> may be bonded together to form a ketone structure (=0); and R^6h and R^6h may be bonded together to form a spirooxyrane structure, provided that the restricted clauses 1 and 2 described above are included. In some embodiments of the compound represented by the formula (H-I), the compound is selected from the group consisting of a compound in which R^2h is hydrogen, R^3h' is hydroxy, both of R^5h and R^5h> are hydrogen, R^6h is methyl, R^6h> is hydroxy, R^7h' is hydroxy, each of R^10h, R^12h and R^16his methyl, both of R^16h> and R^17h> are hydrogen, R^20h is methyl, R^20h> is hydrogen, R^21h' is hydroxy, both of R^21h and R^22h> are hydrogen and R^22h is methyl; a compound in which R^2his hydrogen, R^3h' hydroxy, both of R^5h and R^5h> are hydrogen, R^6h is methyl, R^6h> is hydroxy, R^7h> is acetoxy, each of R^loh, R^12h and R^16h is methyl, both of R^16h> and R^17h' are hydrogen, R^20h is methyl, R^20h' is hydrogen, R^21h> hydroxy, both of R^21h and R^22h' are hydrogen, and R^22h is methyl; a compound in which R^2h is hydrogen, R^3h is hydroxy, both of R^5h and R^5h' are hydrogen, R^6h is methyl, R^6h' is hydroxy, R^7h> is acetoxy, each of R^1Oh, R^12h and R^16h is methyl, both of R^16h> and R^17h' are hydrogen, R^20h is methyl, R^20h> is hydrogen, both of R^21h and R^21h' are bound together to form a ketone structure, R^22h> is hydrogen and R^22h is methyl; a compound in which R^2h is hydrogen, R^3h' is hydroxy, both of R^5h and R^5h> are hydrogen, R^6h is methyl, R^6h' is hydroxy, R^7h' is acetoxy, each of R^10h, R^12h and R^16h is methyl, R^16h> is hydroxy, R^17h> is hydrogen, R^20his methyl, R^20h> is hydrogen, R^21h' is hydroxy, both of R^21h and R^22h are hydrogen, and R^22h is methyl; a compound in which R^2h is hydrogen, R^3h is hydroxy, both of R^5h and R^5h' are hydrogen, R^6h is methyl, R^6h> is hydroxy, R^7h is hydroxy, each of R^10h, R^12h and R^16h is methyl, R^16h' is hydroxy and R^17h' is hydrogen, R^20h is methyl, R^20h> is hydrogen, R^21h> is hydroxy, both of R^21h and R^22h> are hydrogen, and R^22h is methyl; a compound in which R^2h is hydrogen, R^3h> is hydroxy, both of R^5h and R^5h> are hydrogen, R^6h is methyl, R^6h> is hydroxy, R^7h> is hydroxy, each of R^10h, R^12h and R^16h is methyl, both of R^16h> and R^17h> are hydrogen, R^20h is methyl, R^20h> is hydroxy, R^21h> is hydroxy, both of R^21h and R^22h' are hydrogen, and R^22h is methyl; a compound in which R^2h is hydrogen, R^3h is hydroxy, both of R^5h and R^5h are hydrogen, R^6h is methyl, R^6h' is hydroxy, R⁷'^1' is propanoyloxy, each of R^loh, R^12h and R^16h is methyl, both of R^16h' and R^17h> are hydrogen, R^20h is methyl, R^20h> is hydrogen, R^21h> is hydroxy, both of R^21h and R^22h> are hydrogen, and R^22h is methyl; a compound in which R^2h is hydrogen, R^3h is hydroxy, both of R^5h and R^5h are hydrogen, R^6h is methyl, R^6h> is hydroxy, R^7h> is acetoxy, each of R^1Oh, R^12h and R^16h is methyl, both of R^16h> and R^17h> are hydrogen, R^20h is methyl, R^20h> is hydroxy, R^21h' is hydroxy, both of R^21h and R^22h> are hydrogen, and R^22h is methyl; a compound in which R^2h is hydrogen, R^3h is hydroxy, both of R^5h and R^5h are hydrogen, R^6h is methyl, R^6h> is hydroxy, R^7h> is acetoxy, each of R^loh, R^12h and R^16h is methyl, both of R^16h' and R^17h' are hydrogen, R^20h is methyl, R^2Oh> is hydrogen, R^21h> is hydroxy, and each of R^21h, R^22h> and R^22h is hydrogen; a compound in which R is hydrogen, R is hydroxy, R is hydrogen, R is hydroxy, R^6h is methyl, R^6h> is hydroxy, R^7h> is acetoxy, each of R^10h, R^12h and R^16h is methyl, both of R^16h' and R^17h' are hydrogen, R^20h is methyl, R^20h> is hydroxy, R^21h' is hydroxy, both of R^21h and R^22h> are hydrogen, and R^22h is methyl; a compound in which R^2h is hydrogen, R^3h is hydroxy, R^5h is hydrogen , R^5h is acetoxy, R^6h is methyl, R^6h' is hydroxy, R^7h> is acetoxy, each of R^10h, R^12h and R^16h is methyl, both of R^16h> and R^17h> are hydrogen, R^20h is methyl, R^20h> is hydrogen, R^21h> is hydroxy, both of R^21h and R^22h> are hydrogen, and R^22h is methyl; a compound in which R^2h is hydrogen, R^3h' is acetoxy, both of R^5h and R^5h are hydrogen, R^6h is methyl, R^6h' is hydroxy, R^7h> is acetoxy, each of R^10h, R^12h and R^16h is methyl, both of R^16h' and R^17h> are hydrogen, R^20h is methyl, R^20h' is hydrogen, R^21h> is hydroxy, both of R^21h and R^22h' are hydrogen, and R^22h is methyl; a compound in which R^2h is hydrogen, R^3h is hydroxy, both of R^5h and R^5h are hydrogen, R^6h is acetoxymethyl, R^6h' is hydroxy, R^7h> is acetoxy, each of R^10h, R^12h and R^16h is methyl, both of R^16h> and R^17h> are hydrogen, R^20h is methyl, R^20h> is hydrogen, R^21h> is hydroxy, both of R^21h and R^22h> are hydrogen, and R^22h is methyl; a compound in which R^2h is hydrogen, R^3h is hydroxy, both of R^5h and R^5h> are hydrogen, R^6h is methyl, R^6h' is hydroxy, R^7h> is acetoxy, each of R^10h, R^12h and R^16h is methyl, R^16h> is hydrogen, R^17h> are hydroxy, R^20h is methyl, R^20h> is hydrogen, R^21h' is hydroxy, both of R^21h and R^22h> are hydrogen, and R^22h is methyl; a compound in which R^2h is hydrogen, R^3h is hydroxy, both of R^5h and R^5h are hydrogen, R^6h is methyl, R^6h> is hydroxy, R^7h> is acetoxy,

R^12h and R^16h is methyl, both of R^16h> and R^17h' are hydrogen, both of R^20h and R^20h> is hydroxy, R^2Oh> are hydrogen, R^21h' is hydroxy, both of R^21h and R^22h' are hydrogen, and R^22h is methyl; a compound in which R^2h is hydrogen, R^3h is hydroxy, both of R^5h and R^5h are hydrogen, R^6h is methyl, R^6h> is hydroxy, R^7h' is acetoxy, both of R^10h and R^12h are methyl, each of R^16h, R^16h> and R^17h> is hydrogen, R^20h is methyl, R^20h' is hydrogen, R^21h' is hydroxy, both of R^21h and R^22h> are hydrogen, and R^22h is methyl; a compound in which R^2h is hydrogen, R^3h> is hydroxy, both of R^5h and R^5h> are hydrogen, R^6h is methyl, R^6h> is hydroxy, R^7h' is acetoxy, both of R^1Oh and R^12h are methyl, each of R^12h, R^16h> and R^17h' is hydrogen, R^20h is methyl, R^20h> is hydrogen, R^21h> is hydroxy, both of R^21h and R^22h' are hydrogen, and R^22h is methyl; a compound in which R^2h is hydrogen, R^3h is hydroxy, both of R^5h and R^5h are hydrogen, R^6h is methyl, R^6h> is hydroxy, R^7h> is acetoxy, both of R^12h and R^16h are methyl, each of R^1Oh, R^16h' and R^17h> is hydrogen, R^20h is methyl, R^20h> is hydrogen, R^21h> is hydroxy, both of R^21h and R^22h> are hydrogen, and R^22h is methyl; a compound in which R^2h is hydrogen, R^3h is hydroxy, both of R^5h and R^5h> are hydrogen, R^6h is acetoxymethyl, R^6h> is hydroxy, R^7h' is hydroxy, each of R^10h , R^12h, and R^16h is methyl, both of R^16h> and R^17h> are hydrogen, R^20h is methyl, R^20h> is hydrogen, R^21h> is hydroxy, both of R^21h and R^22h> are hydrogen, and R^22h is methyl; a compound in which R^2h is hydrogen, R^3h is hydroxy, both of R^5h and R^5h' are hydrogen, R^6h is methyl, R^6h> is hydroxy, R^7h' is hydroxy, each of R^10h R^12h and R^16his methyl, both of R^16hand R^17h> are hydrogen, R^20h is methyl, R^20h> is hydrogen, R^21h and R^21h> are bound together to form a ketone structure, R^22h is hydrogen, and R^22h is methyl; a compound in which R^2h is hydrogen, ^R3h is hydroxy, each of R^5h, R^5h' and R^6h is hydrogen, R^6h' is acetoxy, R^7h> is hydroxy, each of R^10h, R^12h and R^16h is methyl, both of R^16h> and R^17' are hydrogen, R^20h is methyl, R^20h is hydrogen, R^21h> is hydroxy, both of R^21h> and R^22h> are hydrogen, and R^22h is methyl; a compound in which R^2h is methyl, R^3h is hydroxy, both of R^5h and R^5h are hydrogen, R^6h is methyl, R^6h> is hydroxy, R^7h> is hydroxy, each of R^1Oh, R^12h and R^16h is methyl, both of R^16h and R^17h> are hydrogen, R^2Oh is methyl, R^20h> is hydrogen, R^21h> is hydroxy, both of R^21h and R^22h' are hydrogen, and R^22h is methyl; a compound in which R^2h is methyl, R^3h is hydroxy, both of R^5h and R^5h are hydrogen, R^6h is methyl, R^6h' is hydroxy, ^R7h> is acetoxy, each of R^10h, R^12h and R^16his methyl, both of R^16h> and R^17h' are hydrogen, R^20h is methyl, R^2Oh> is hydrogen, R^21h' is hydroxy, both of R^21h and R^22h> are hydrogen, and R^22h is methyl; a compound in which R^2h is hydrogen, R^3h> is hydroxy, R^5h is hydrogen, R^5h' is hydroxy, R^6h is methyl, R^6h> is hydrogen, R^7h> is acetoxy, each of R^1Oh, R^12h and R^16h> is methyl, both of R^16h> and R^17h' are hydrogen, R^20h is methyl, R^20h' is hydrogen, R^21h> is hydroxy, both of R^21h and R^22h' are hydrogen, and R^22h is methyl; a compound in which R^2h is hydrogen, R^3h> is hydroxy, each of R^5h, R^5h> R^6h and R^6h' is hydrogen, R^7h> is hydroxy, each of R^10h, R^12h and R^16his methyl, both of R^16h> and R^17h' are hydrogen, R^20h is methyl, R^20h> is hydrogen, R^21h> is hydroxy, both of R^21h and R^22h> are hydrogen, and R^22h is methyl; a compound in which R^2h is hydrogen, R^3h is hydroxy, both of R^5h and R^5h are hydrogen, R^6h and R^6h' are bound together to form a spirooxyrane structure, R^7h is acetoxy, each of R^10h, R^12h and R^16h is methyl, both of R^21h and R^22h> are hydrogen, R^20h is methyl, R^20h> is hydrogen, R^21h' is hydroxy, both of R^21h and R^22h' are hydrogen, and R^22h is methyl; a compound in which R^2h is hydrogen, R^3h is hydroxy, both of R^5h and R^5h are hydrogen, R^6h and R^6h are bound together to form a spirooxyrane structure, R^7h is hydroxy, each of R^10h, R^12h and R^16h is methyl, both of R^16h> and R^17h' are hydrogen, R^2Oh is methyl, R^20h' is hydrogen, R^21h> is hydroxy, both of R^21h and R^22h> are hydrogen, and R^22h is methyl; a compound in which R^2h is hydrogen, R^3h' is hydroxy, both of R^5h and R^5h are hydrogen, R^6h is methyl, R^6h' is acetoxy, R^7h> is acetoxy, each of R^10h, R^12h and R^16h is methyl, both of R^16h> and R^17h' are hydrogen, R^20h is methyl, R^20h> is hydrogen, R^21h> is hydroxy, both of R^21h and R^22h> are hydrogen, and R^22h is methyl; a compound in which R^2h is hydrogen, R^3h is hydroxy, both of R^5h and R^5h are hydrogen, R^6h is methyl, R^6h' is hydroxy, R^7h> is acetoxy, each of R^10h, R^12h and R^16h is methyl, R^16h' is hydroxyl, R^17h> is hydrogen, R^20h is methyl, R^20h' is hydrogen, R^21h and R^21h' are bound together to form a ketone structure, R^22h is hydrogen, and R^22h is methyl; a compound in which R^2h is hydrogen, R^3h is hydroxy, both of R^5h and R^5h are hydrogen, R^6h is methyl, R^6h> is hydroxy, R^7h> is acetoxy, each of R^10h, R^12h and R^16h is methyl, both of R^16h' and R^17h> are hydrogen, R^20h is methyl, R^20h' is hydrogen, R^21h is hydrogen, both of R^21h' and R^22h> are hydroxy, and R^22h is methyl; a compound in which R^2h is hydrogen, R^3h is hydroxy, R^5h is hydrogen, R^5h is hydroxy, R^6h methyl, R^6h> is hydroxy, R^7h' is acetoxy, each of R^1Oh, R^12h and R^16h is methyl, both of R^16h and R^17h' are hydrogen, R^20h is methyl, R^2Oh' is hydrogen, R^21h is hydrogen, both of R^21h> and R^22h' are hydroxy, and R^22h is methyl; a compound in which R^2h is hydrogen, R^3h is hydroxy, both R^5h and R^5h are hydrogen, R^6h is methyl, R^6h> is hydroxy, R^7h> is hydroxy, both of R^1Oh and R^16h are methyl, each of R^12h, R^16h' and R^17h' is hydrogen, R^20h is methyl, R^20h> is hydrogen, R^21h' is hydroxy, both of R^21h and R^22h> are hydrogen, and R^22h is methyl; and a compound in which R^2h is hydrogen, R^3h is hydroxy, both of R^5h and R^5h are bound together to form a ketone structure, R^6h is methyl, R^6h is hydroxy, R^7h is acetoxy, each of R^10h, R^12h and R^16h is methyl, both of R^16h> and R^17h' are hydrogen, R^20h is methyl, R^20h> is hydrogen, R^21h> is hydroxy, both of R^21h and R^22h> are hydrogen, and R^22h is methyl. In another embodiment, the macrolide compound is the compound of formula "H-II" or a pharmaceutically acceptable salt or hydrate thereof:

In the formula (H-II), R^2h, R^6h, R^1Oh, R^16h, R^2Oh, R^21h, R^23h and are the same as or different from each other and each represents (1) hydrogen, (2) methyl, (3) hydroxymethyl or (4) C_2-8 acyloxymethyl; R^3h', R^6h>, R^7h>, R^16h>, R^17h>, R^20h>, R^21h' and R^22h> are the same as or different from each other and each represents (1) hydrogen, (2) hydroxy, (3) methoxy or (4) C_2-8 acyloxy; further, R^21h and R^21h' may be bonded together to form a ketone structure (=0); and further, R^6h and R^6h may be bonded together to form a spirooxyrane structure. In some embodiments of a macrolide compound of formula H-II, the compound is selected from the group consisting of a compound in which R^2h is hydrogen, R^3h is hydroxy, R^6h is methyl, R^6h> is hydroxy, R^7h' is acetoxy, each of R_loh, R^12h and R^16h is methyl, both of R^16h> and R^17h>, are hydrogen, R^20h methyl. R^2Oh> is hydrogen, R^21h' is hydroxy, both of R^21h and R^21h> are hydrogen and R^22h is methyl; a compound in which R^2h is hydrogen, R^3h is hydroxy, R^6h is methyl, R^6h is hydroxy, R^7h> is hydroxy, each of R^1Oh, R^12h and R^16h is methyl, both of R^16h' and R^17h> are hydrogen, R^20h is methyl, R^20h> is hydrogen, R^21h' is hydroxy, both of R^21h and R^21h> are hydrogen, and R^22h is methyl; a compound in which R^2h is hydrogen. R^3h is hydroxy, R^6h is methyl, R^6h is hydroxy, R^7h' is acetoxy, each of R^10h, R^12h and R^16h is methyl, both of R^16h> and R^17h> are hydrogen, R^20h is methyl, R^20h> is hydrogen, R^21h and R^21h> are bound together to form a ketone structure, R^22h' is hydrogen, and R^22h is methyl; a compound in which R^2h is hydrogen. R^3h' is hydroxy, R^6h and R^6h are bound together to form a spirooxyrane structure, R^7h is acetoxy, each of R^10h, R^12h and R^16h is methyl, both of R^16h> and R^17h> are hydrogen, R^20h is methyl, R^20h> is hydrogen, R^21h' is hydroxy, both of R^21h and R^22h> are hydrogen, and R^22h is methyl; a compound in which R^2h is hydrogen. R^3h is hydroxy, R^6h is methyl, R^6h> is acetoxy, R^7h> is acetoxy, each of R^10h, R^12h and R^16h is methyl, both of R^16h> and R^17h> are hydrogen, R^20h is methyl, R^20h> is hydrogen, R^21h> is hydroxy, both of R^21h and R^22h' are hydrogen, and R^22h is methyl; and a compound in which R^2h is hydrogen, R^3h is hydroxy, R^6h is methyl, R^6h> is hydroxy, R^7h> is acetoxy, each of R^1Oh, R^12h and R^16h is methyl, R^16h> is hydrogen, R^17h> is hydroxy, R^20h is methyl, R^20h> is hydrogen, R^21h' is hydroxy, both of R^21h and R^22h' are hydrogen, and R^22h is methyl. In another embodiment, the macrolide compound is the compound of formula "H-III" or a pharmaceutically acceptable salt or hydrate thereof:

In the formula, R²\ R^5h, R^6h, R^1Oh, R^12h, R^16h, R^20h, R^21h and R^22h are the same as or different from each other and each represents (1) hydrogen, (2) methyl, (3) hydroxymethyl or (4) C_2-8 acyloxymethyl; R^5h>, R^6h', R^7h', R^16h', R^17h>, R^20h', R^21h> and R^22h> are the same as or different from each other and each represents (1) hydrogen, (2) hydroxy, (3) methoxy or (4) C_2-8 acyloxy; further, R^5h and R^5h may be bonded together to form a ketone structure (=0); further, R^21h and R^21h may be bonded together to form a ketone structure (=0); further, R^6h and R^6h' may be bonded together to form a spirooxyrane structure. In some embodiments of a compound of formula H-III, the macrolide is selected from the group consisting of a compound in which R^2h is hydrogen, both of R^5h and R^5h are hydrogen, R^6h is methyl, R^6h' is hydroxy, R^7h> is hydroxy, each of R^loh, R^12h and R^16h is methyl, both of R^16h> and R^17h> are hydrogen, R^20h is methyl, R^20h' is hydrogen, R^21h> is hydroxy, both of R^21h and R^22h> are hydrogen and R^22h is methyl; a compound in which R^2h is hydrogen, both of R^5h and R^5h' are hydrogen, R^6h is methyl, R^6h> is hydroxy, R^7h> is acetoxy, each of R^10h, R^12h and R^16h is methyl, both of R^16h> and R^17h' are hydrogen, R^20h is methyl, R^20h' is hydrogen, R^21h' is acetoxy, both of R^21h and R^22h' are hydrogen and R^22h is methyl; and a compound in which R^2h is hydrogen, both of R^5h and R^5h are hydrogen, R^6h is methyl, R^6h> is hydroxy, R^7h' is acetoxy, each of R^10h, R^12h and R^16h is methyl, both of R^16h' and R^17h> are hydrogen, R^2Oh is methyl, R^20h> is hydrogen, R^21h> is hydroxy, both of R^21h and R^22h' are hydrogen and R^22h is methyl. In another embodiment, the macrolide compound is the compound of formula "H-IV" or a pharmaceutically acceptable salt or hydrate thereof:

In the formula, R^2h, R^3h, R^4h, R^5h, R^6h, R^7h, R^1Oh, R^12h, R^16h, R^20h, R^21h and R^22h are the same as or different from each other and each represents (1) hydrogen, (2) methyl, (3) hydroxymethyl or (4) C_2-8 acyloxymethyl; R^3h>, R^5h>, R^611', R^7h', R^16h>, R^17h>, R^20h', R^21h> and R^22h> are the same as or different from each other and each represents (5) hydrogen, (6) hydroxy, (7) methoxy or (8) C_2-8 acyloxy; further, R^3h and R^3h may be bonded together to form a ketone structure (=0); further, R^5h and R^5h> may be bonded together to form a ketone structure (=0); further, further, R^7h and R^7h> may be bonded together to form a ketone structure (=0); R^21h and R^21h may be bonded together to form a ketone structure (=0); further,

represent , R^5h> is hydrogen, R^6h is methyl, R^6h> is hydroxy, R^7h is hydrogen, R^7h' is acetoxy, each of R^1Oh, R^12h and R^16h is methyl, both of R^16h' and R^17h> are hydrogen, R^20h is methyl, R^20h> is hydrogen, R^21h> is hydroxy, both of R^21h and R^22h are hydrogen, and R^22h is methyl; and a compound in which R^2h is hydrogen, R^3h is hydrogen, R^3h' is hydroxy, each of R^4h, R^5h and R^5h' is hydrogen, R^6h is methyl, R^6h' is hydroxy, R^7h and R^7h' are bound together to form a ketone structure, each of R^1Oh, R^12h and R^16h is methyl, both of R^16h' and R^17h> are hydrogen, R^20h is methyl, R^20h' is hydrogen, R^21h' is hydroxy, both of R^21h and R^22h> are hydrogen, and R^22h is methyl. In another embodiment, the macrolide compound is the compound of formula "H-V" or a pharmaceutically acceptable salt or hydrate thereof:

In the formula (H-V), R^12h, R^16h, R^16h>, R^17h>, R^20h, R^2Oh> and R^21h' have the same meanings as the definitions in formula (H-I) described above; R represents hydrogen or methyl; R^21h represents hydrogen, methyl or ethyl; and G^mh is represented by the formula (MH-I):

(wherein R^2h, R^3h>, R^5h, R^5h>, R^6h, R^6h>, R^7h', and R^10h have the same meanings as the definitions in formula (H-I)), the formula (MH-II):

(wherein R^2h, R^3h>, R^6h, R^6h>, R^7h> and R^loh have the same meanings as the definitions in formula (H-II) described above), the formula (MH-III):

(wherein R^2h, R^5h, R^5h', R^6h, R^6h>, R^7h' and R^1Oh have the same meanings as the ' definitions in formula (H-III) described above), the formula (MH-IV):

(wherein R^2h, R^6h, R^7h and R^1Oh have the same meanings as the definitions in the formula (H-I)), or the formula (MH-V):

(wherein R^2h, R^3h , R^6h, R^6h and R^1Oh have the same meanings as the definitions in formula (H-I)), provided that the restricted clauses land 2 described above are included. In some embodiments of the compound according to formula H-V, the compound is selected from the group consisting of a compound in which G^mh is represented by the formula (MH-I), R^2h is hydrogen, R^3h> is hydroxy, both of R^5h and R^5h> are hydrogen, R^6h is methyl, R^6h' is hydroxy, R^7h> is acetoxy, each of R^10h, R^12h and R^16h is methyl, each of R^16h', R^17h' and R^18h is hydrogen, each of R^20h, R^21h' and ^^lh" is hydrogen and R^20h> is hydroxy; a compound in which G^mh is represented by the formula (MH-I), R^2h is hydrogen, R^3h is hydroxyl, both of R^5h and R^5h' are hydrogen, R^6h is methyl, R^6h' is hydroxyl, R^7h' is acetoxy, each of R^10h, R^12h and R^16h is methyl, R^16h> is hydrogen, R^17h> is hydroxyl, and each of R^18h, R^20h, R^20h', R^21h> and R^21h" is hydrogen; a compound in which G^mh is represented by the formula (MH-I), R^2h is hydrogen, R^3h is hydroxyl, both of R^5h and R^5h' are hydrogen, R^6h is methyl, R^6h> is hydroxyl, R^7h> is acetoxy, each of R^1Oh, R^12h and R^16h is methyl, R^16h' is hydrogen, R^17h> is hydroxyl, R^18h is methyl, and each of R^20h, R^20h', R^21h> and R^21h" is hydrogen; a compound in which G^mh is represented by the formula (MH-I), R^2h is hydrogen, R^3h> is hydroxy, both of R^5h and R^5h' are hydrogen, R^6h is methyl, R^6h' is hydroxy, R^7h> is acetoxy, each of R^1Oh, R^12h and R^16h is methyl, R^16h> is hydrogen, R^17h' is hydroxy, R^18h is methyl, and each of R^20h, R^2Oh>, R^21h' and R^21h" is hydrogen; a compound in which G^mh is represented by the formula (MH-V), R^2h is hydrogen, R^3h> is hydroxyl, R^6h is methyl, R^6h> is hydroxyl, each of R^loh, R^12h and R^16h is methyl, each of R^16h>, R^17h>, R^18h and R^20h> is hydrogen, R^20h is methyl, R^21h> is hydroxy, and R^21h" is ethyl. In another embodiment, the macrolide compound is the compound of formula "H-VI" or a pharmaceutically acceptable salt or hydrate thereof:

In the formula, R^12h, R^16h, R^16h', R^17h>, R^20h, R^20h>, R^21h, R^21h', R^22h and R^22h> have the same meanings as the definitions in formula (H-I); G^mh has the same meaning as the definition in formula (H-V) described above. In some embodiments of the compound according to formula H-VI, the compound is selected from the group consisting of a compound in which G^mh is represented by the formula (MH-I), R^2h is hydrogen, R^3h> is hydroxy, both of R^5h and R^5h> are hydrogen, R^6h is methyl, R^6h' is hydroxy, R^7h' is acetoxy, each of R^1Oh, R^12h and R^16h is methyl, both of R^16h> and R^17h> are hydrogen, R^20h is methyl, both of R^20h> and R^21h are hydrogen, both of R^21h' and R^22h> are hydroxy, and R^22h is methyl; and a compound in which G^mh is represented by the formula (MH-I), R^2h is hydrogen, R^3h is hydroxy, both of R^5h and R^5h' are hydrogen, R^6h is methyl, R^6h> is hydroxy, R^7h> is acetoxy, each of R^1Oh, R^12h and R^16h is methyl, both of R^16h* and R^17h' are hydrogen, R^20h is methyl, each of R^20h', R^21h and R^22h> is hydrogen, R^21h> is hydroxy, and R^22h is methyl. In another embodiment, the macrolide compound is the compound of formula "H- VII" or a pharmaceutically acceptable salt or hydrate thereof:

In the formula, G™*¹ has the same meaning as the definition in formula (H-V); — represents a single bond or a double bond; and R^12h, R^16h, R^16h>, R^17h>, R^20h, R^20h>, R^21h, R^21h>, R^22h and R^22h> have the same meanings as the definitions in formula (H-I). In some embodiments, the compound according to formula H-VII is selected from the group consisting of a compound in which G^mh is represented by the formula (MH-I), — represents a double bond, R^2h is hydrogen, R^3h is hydroxy, both of R^5h and R^5h> are hydrogen, R^6h is methyl, R^6h> is hydroxy, R^7h> is acetoxy, each of R^1Oh, R^12h and R^16h is methyl, both of R^16h' and R^17h' are hydrogen, R^20h> is methyl, each of R^20h', R^21h and R^22h> is hydrogen, R^21h' is hydroxy, and R^22h is methyl; and a compound in which G^mh is represented by the formula (MH-I), — represents a single bond, R^2h is hydrogen, R^3h> is hydroxy, both of R^5h and R^5h> are hydrogen, R^6h is methyl, R^6h> is hydroxy, R^7h> is acetoxy, each of R^1Oh, R^12h and R^16h is methyl, both of R^16h> and R^17h> are hydrogen, R^20h is methyl, each of R^2Oh', R^21h and R^22h> is hydrogen, R^21h> is hydroxy, and R^22h is methyl; and a compound in which G"* is represented by the formula (MH-II), — represents a double bond, R^2h is hydrogen, R^3h> is hydroxy, R^6h is methyl, R^6h> is hydroxy, R^7h' is acetoxy, each of R^loh, R^12h and R^16h is methyl, both of R^16h> and R^17h> are hydrogen, R^20h is methyl, each of R^20h', R^21h and R^22h> is hydrogen, R^21h' is hydroxy, and R^22h is methyl. In another embodiment, the macrolide compound is the compound of formula "H- VIII" or a pharmaceutically acceptable salt or hydrate thereof:

In the formula, G^mh, R^12h, R^16h, R^16h', R^17h', R^20h, R^22h and R^22h' have the same meanings as formula (H-I); and R^18h represents hydrogen or hydroxy. In some embodiments, the macrolide compound according to formula H-VIII is selected from the group consisting of a compound in which G^mh is represented by the formula (MH-I), R^2h is hydrogen, R^3h> is hydroxy, both of R^5h and R^5h> are hydrogen, R^6h is methyl, R^6h> is hydroxy, R^7h> is acetoxy, each of R^1Oh, R^12h and R^16h is methyl, both of R^16h' and R^I7h' are hydrogen, R^18h' is hydroxy, R^2Oh is methyl, R^22h> is hydroxy, and R^22h is methyl; and a compound in which G^mh is represented by the formula (MH-I), R^2h is hydrogen, R^3h is hydroxy, both of R^5h and R^5h> are hydrogen, R^6h is methyl, R^6h' is hydroxy, R^7h' is acetoxy, each of R^10h, R^12h and R^16h is methyl, both of R^16h' and R^17h> are hydrogen, R^18h' is hydroxy, R^20h is methyl, R^22h' are hydrogen, and R^22h is methyl. In another embodiment, the macrolide compound is the compound of formula "H-IX" or a pharmaceutically acceptable salt or hydrate thereof:

In the formula, G^mh has the same meaning as the definition in formula (H-V); C^14~C¹⁵ and C¹⁶⁼C¹⁷ are the same as or different from each other and each represents a single bond or a double bond; R^12h, R^16h and R^18h have the same meanings as the definition in formula (H- V); R^14h represents hydrogen or methyl; R^18h represents hydrogen or hydroxy; R^19h and R^19h> are (1) the same as or different from each other and each represents hydrogen, methyl or hydroxy, or (2) R^19h and R^19h are bound together to represent a ketone structure (=0). In some embodiments, the macrolide compound according to formula H-IX is selected from the group consisting of a compound in which G^mh is represented by the formula (MR-I), C¹⁴^C¹⁵ is a double bond, C¹⁶⁼C¹⁷ is a single bond, R^2h is hydrogen, R^3h' hydroxy, both of R^5h and R^5h> are hydrogen, R^6h is methyl, R^6h' is hydroxy, R^7h' is acetoxy, each of R^1Oh, R^12h and R^16h is methyl, each of R^14h, R^18h and R^19h is hydrogen, and both of R^18h> and R^19h> are hydroxy; a compound in which G"* is represented by the formula (MH-i),C^14~C¹⁵ is a single bond, C¹⁶-C¹⁷ is a double bond, R^2h is hydrogen, R^3h' is hydroxy, both of R^5h and R^5h> are hydrogen, R^6h is methyl, R^6h> is hydroxy, R^7h' is acetoxy, both of R^loh and R^14h are methyl, both of R^12h and R^16h are hydrogen, R^18h is methyl, R^18h> is hydroxy, and R^19h and R^19h> are bound together to form a ketone structure (=0); and a compound in which G"* is represented by the formula (MH-I), C^14~C¹⁵ is a single bond, C^16"C¹⁷ is a double bond, R^2h is hydrogen, R^3h> is hydroxy, both of R^5h and R^5h> are hydrogen, R^6h is methyl, R^6h> is hydroxy, R^7h' is acetoxy, both of R^10h and R^14h are methyl, both of R^12h and R^16h are hydrogen, R^18h is methyl, R^18h> is hydroxy, R^19h is hydrogen, and R^19h' is hydroxy. In another embodiment, the macrolide compound is the compound of formula "H-X" or a pharmaceutically acceptable salt or hydrate thereof:

In the formula, G"*, R^16h and R^17h> have the same meanings as the definitions in formula (H-V); R^14h represents hydrogen or methyl; C^14"C¹⁵ and C¹⁶⁼C¹⁷ are the same as or different from each other and each represents a single bond or a double bond; R^18h is hydrogen or hydroxy; and R^18h represents (1) methyl or (2) the formula (R-F). In some embodiments, the macrolide compound according to formula H-VTII is selected from the group consisting of a compound in which G^mh is represented by the formula (MH-I), R^18h" is represented by the formula (R-F), C¹⁴⁼C¹⁶ is a double bond, C^16~C¹⁷ is a single bond, R2h is hydrogen, R^3h' is hydroxy, both of R^5h and R^5h' are hydrogen, R^6h is methyl, R^6h' is hydroxy, R^7h> is acetoxy, each of R^1Oh, R^12h and R^16h is methyl, both of R^14h and R^17h> are hydrogen, R^18h> is hydroxy, both of R^Ga and R^β are methyl, both of R^βb and R^f4b are hydrogen, and R^f4b is hydroxy; a compound in which G"* is represented by the formula (MH-I), C^14~C¹⁵ is a single bond, C^16"C¹⁷ is a double bond, R^2h is hydrogen, R^3h> is hydroxy, both of R^5h and R^5h> are hydrogen, R^6h is methyl, R^6h' is hydroxy, R^7h> is acetoxy, both of R^1Oh and R^14h are methyl, each of R^12h, R^16h and R^17h> is hydrogen, R^18h' is hydroxy, and R^18h" is methyl; and a compound in which Gmh is represented by the formula (MH-I), C^14"C¹⁵ is a double bond, C¹⁶-^"C¹⁷ is a single bond, R^2h is hydrogen, R^3h> is hydroxy, both of R^5h and R^5h> are hydrogen, R^6h is methyl, R^6h> is hydroxy, R^7h> is acetoxy, each of R^10h, R^12h and R^16h is methyl, both of R^14h and R^18h> are hydrogen, R^17h> is hydroxy, and R^18h" is methyl. In another embodiment, the macrolide compound is the compound of formula "H-XI" or a pharmaceutically acceptable salt or hydrate thereof:

In the formula, G""¹ and R^1Zh have the same meanings as the definitions in formula (H-V); R^16h represents hydrogen, methyl or hydroxy; and R^17h represents (1) hydrogen or (2) the formula (R-F). In some embodiments, the macrolide compound according to formula H-VIII is selected from the group consisting of a compound in which G^mh is represented by the formula (MH-I), R^17h" is represented by the formula (R-F), R^2h is hydrogen, R^3h' is hydroxy, both of R^5h and R^5h> are hydrogen, R^6h is methyl, R^6h> is hydroxy, R^7h> is acetoxy, each of R^10h, R^12h a mned R^16h" is methyl, both of R^βa and R^f4a are hydroxy, R^βb is hydrogen, R^f4b is methyl, and R^β is ethyl; and a compound in which G^mh is represented by the formula (MH-I), R^2h is hydrogen, R^3h is hydroxy, each of R^5h, R^5h> and R^6h> is hydrogen, R^6h is methyl, R^7h' is acetoxy, both of R^10h and R^12h are methyl, R^16h" is hydroxy, and R^17h" is hydrogen. In another embodiment, the macrolide compound is the compound of formula 15 or a pharmaceutically acceptable salt or hydrate thereof:

In the formula (15), G^mr is represented by the formula (MD-I):

(wherein R^2r, R^3r', R^5r, R^5r>, R^6r, R^6r>, R^7r' and R^1Or are the same as or different from each other and each represents 1) hydrogen, 2) methyl which may have substituents, 3) -OR^H (wherein R^H is <1> hydrogen, <2> methyl or <3> acetyl), 4) -OR^D (wherein R^D represents <1> C_1-22 alkyl (provided that in case of methyl, it has always substituents), <2> -CH₂Ar, <3> C_3-22 acyl, <4> unsaturated C_3-22 acyl, <5> -COR^CO, <6> C_1-22 alkylsulfonyl, <7> benzenesulfonyl or <8> -SiR^slR^S2R^S3, each of which may have substituents) 5) halogen or 6) -R^M-NR^N1R^N2 (Ar, R^co, R^sl, R^S2, R^S3, R^M, R^N1 and R^N2 have the same meanings as the definitions of formula 5), further, R^5r and R^5r may be bonded together to represent a ketone structure; further, R^6r or R^6r may be bonded together to represent a spirooxyrane structure or an exo- methylene structure; further, either of R^6r or R^6r , and R^7r may be bonded together to represent a 1,3-dioxolane ring), the formula (MD-II):

(wherein R j2^/r^r, τ R>3"r' , τ R>6^or^r, _D R6^or^r' , τ R>7^/r^r' and R^1Or have the same meanings as the above-mentioned definition), the formula (MD-III):

(wherein R^2r, R^5r, R^5r', R^6r, R^6r>, R^7r' and R^1Or have the same meanings as the above-mentioned definition), the formula (MD-IV):

(wherein R ,2r ^r, τ Rj6r , τ R_>7r ^r' , and R , 1Or ^r - have the same meanings as the above-mentioned definition), or the formula (MD-V):

(wherein R }2r , τ R>3r' , τ R>6r₉ R -nδr' and R , 1Or have the same meanings as the above-mentioned definition); R^12r, R^16r, R^16r', R^17r>, R^18r, R^2Or, R^2Or>, R^21r, R^21r>, R^22r and R^22r' are the same as or different from each other and each represents 1) hydrogen, 2) methyl which may be optionally substituted. 3) -OR^H (wherein R^H represents <1> hydrogen, <2> methyl or <3> acetyl), 4) -OR^D (wherein R^H represents <1> C_1-22 alkyl (provided that in case of methyl, it has always substituents), <2> CH₂Ar, <3> C_3-22 acyl, <4> unsaturated C_3-22 acyl, <5> -COR^CO, <6> C_1-22 alkylsulfonyl, <7> benzenesulfonyl, or <8> -SiR^slR^S2R^S3, each of which may have substituents), 5) halogen or 6) -R^M-NR^N1R^N2 (Ar, R^co, R^S1, R^S2, R^S3, R^M, R^N1 and R^N2 have the same meanings as the definitions in formula 5); further, R^21r and R^21r may be bonded together to represent <1> a ketone structure (=0) or an oxime structure (=NOR^OX: wherein R^ox has the same meaning as the definition in formula 5); when either one of A and B is 1) halogen, or 2) <1> alkylsulfonyloxy, <2> benzenesulfonyloxy or <3> C_1-22 alkoxy, each of which may have substituents, the other is 1) hydroxy, or 2) <1> C_1-22 alkoxy or <2> C_2-22 acyloxy, each of which may have substituents. In another embodiment, the macrolide compound is the compound of formula 16 or a pharmaceutically acceptable salt or hydrate thereof:

In the formula (16) , R^3r>, R^5r, R^5r>, R^6r, R^6r', R^H, R^17r>, R^20r, R^20r', R^21r, R^21r', R^22r and R^22r' have the same meanings as the definitions in formula 15; and R^2s, R^1Os, R^12s, R^16s and R^I8s are the same as or different from each other and each represents hydrogen or methyl. In another embodiment, the macrolide compound is the compound of formula 17 or a pharmaceutically acceptable salt or hydrate thereof:

In the formula (17) , R^Jr , R^3r, R^3r , R^or, R^M , R^/r , R^{1 n} , R^2ϋr, R^2υr , R^22r and R^22r have the same meanings as the definitions in formula 15; and R^2s, R^1Os, R^16s, R^16s and R^18s have the same meanings as the definitions in formula 16. In another embodiment, the macrolide compound is the compound of formula 18 or a pharmaceutically acceptable salt or hydrate thereof:

In the formula (18), R , 17s ^s' represents hydrogen or hydroxy; R represents hydrogen or methyl; R ,21s¹ represents hydroxy or methoxy; and R AM . represents -NR³¹¹¹¹R²"¹² (wherein R >a^! ml and R^am2 are (1) the same as or different from each other and each represents 1) hydrogen, or 2) <1> C_1-22 alkyl, <2> C_3-8 cycloalkyl, <3> unsaturated C_3-22 alkyl, <4> C_2-22 acyl, <5> unsaturated C_3-22 acyl, <6> C_6-I4 aryl, <7> C_3-8 cycloalkenyl, <8> 5-membered to 14- membered heteroaryl, <9> aralkyl, <10> heteroaralkyl, <11> C 1-22 alkylsulfonyl, <12> benzenesulfonyl, <13> azetidin-2-yl, <14> pyrrolidin-3-yl, <15> piperazin-4-yl or <16>homopiperazin-4-yl, each of which may have substituents, or (2) -NR^amlR^am2 is bound together to represents an optionally substituted 3-membered to 14-membered nitrogen- containing non-aromatic heterocyclic ring). In some embodiments of the compound according to formula 18, the compound is selected from the group of compounds consisting of, (1) a compound in which R^AM is represented by

, and further which may optionally have one to four of substituents selected from hydroxy, amino, N-methylamino, N-ethylamino, N,N-dimethylamino, N₅N- diethylamino, N-ethyl-N-methylamino, azetidin-1-yl, pyrrolidin-1-yl, piperidin-1-yl, morpholin-1-yl, thiomorpholin-1-yl, piperazin-1-yl, 4-methylpiperazin-l-yl, 4-ethylpiperazin- 1-yl, N-(2-hydroxyethyl)amino, N-(3-hydroxypropyl) amino, N-(2-hydroxyethyl)-N- methylamino, N-(3-hydroxypropyl)-N-methylamino, N-(2-hydroxyethyl)-N-ethylamino or N- (3-hydroxypropyl)-N-ethylamino; (2) a compound in which R^AM is represented by

and further, which may optionally have one to four of substituents selected from methyl, ethyl, n-propyl, hydroxy, hydroxymefhyl, 2-hydroxyethyl and 3-hydroxypropyl; and (3) a compound in which R^AM is represented by

, and further, which may optionally have one or two of substituents selected from methyl, ethyl, n-propyl, hydroxy, hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl, amino, N-methylamino, N-ethylamino, N,N-dimethylamino, N,N-diethylamino, N-ethyl-N-methylamino, azetidin-1-yl, pyrrolidin-1- yl, piperidin-1-yl, morpholin-1-yl and thiomoφholin-1-yl. In another embodiment, the macrolide compound is the compound of formula 19 or a pharmaceutically acceptable salt or hydrate thereof:

In the formula, G^mr and R^12r have the same meanings as the definitions in formula

(15); and Z represents oxygen or the formula:

(wherein R^z represents (1) hydrogen or (2) a and Ci_-8 alkyl, C^1"8 alkenyl or C^1'8 alkynyl which may have substituents and an epoxy structure). In another embodiment, the macrolide compound is the compound of formula 20 or a pharmaceutically acceptable salt or hydrate thereof:

In the formula (20), A' and B' are bound together with oxygen to represent an epoxy structure, or either one of them represents hydroxy and the other represents any one of chlorine, bromine, hydroxy and methoxy; R^21a and R^21b' are bound together with oxygen to represent a ketone structure, or either one of them represents hydrogen and the other represents any one of hydroxy, methoxy and -OR^m; R³ , R⁶ and R⁷ are the same as or different from each other and each represents hydrogen, acetyl or -R^m; R¹⁶, R¹⁷ and R²⁰ are the same as or different from each other and each represents hydrogen, hydroxy or -OR^m; R¹² represents methyl, -CH₂OH or -CH₂OR^m (wherein R^m represents Ci-C₈ alkyl, C_2-C₈ acyl, R^bnCH₂, R^bnCO or R¹¹¹R¹¹²NCO; R^bn represents C_6-Ci₀ aryl or C_5-C₁₄ heteroacyl. which may optionally have one or more substituents described below, R^nl and Rⁿ² are the same as or different from each other and each represents hydrogen, Ci-C₈ alkyl, C_3-C₇ cycloalkyl, benzyl which may optionally have one or more substituents described below, or R^πl and Rⁿ² are bound together to represent pyrrolidine, piperidine, piperazine, N-substituted piperazine or morpholine; The substituent described here indicates the following: a) Ci-C₈ alkyl, Ci-C₈ alkoxy, C_2-C₈ acyl, b) fluoro, chloro, bromo, iodo, c) carboxylic acid, sulfonic acid, carboxylic acid ester, carboxamide (which may optionally have substituents on the nitrogen), d) nitro, amino, N-monosubstituted amino, N, N-disubstituted amino, e) a hydroxy group, mercaptane, Ci-C₈ alkylthio, Ci-C₈ alkylsulfoxide, Ci-C₈ alkylsulfone, provided that the restricted clauses 1 and 2, described above, are included. In another embodiment, the macrolide compound is the compound of formula 21 or a pharmaceutically acceptable salt or hydrate thereof:

In the formula (21), R³ and R⁶ represent hydrogen; R⁷ represents hydrogen or acetyl; R¹⁶, R¹⁷ and R²⁰ are the same as or different from each other and each represents hydrogen or hydroxy; R^21a and R^21b are bound together with oxygen to represent a ketone structure, or either one of them represents hydroxy or methoxy and the other represents hydrogen; and R¹² represents methyl or -CH₂OH, provided that the restricted clauses 1 and 2, described above, are included. In one embodiment of a compound according to formula 21, R³ , R⁶ and R¹⁷ are hydrogen; R⁷ is hydrogen or acetyl; R¹⁶ and R²⁰ are the same as or different from each other and each represents hydrogen or hydroxy; R^21a and R^21b are bound together with oxygen, or either one of them represents hydroxy and the other is hydrogen; and R¹² is methyl. In another embodiment of a compound according to formula 21 , R³ , R⁶ and R¹⁷ are hydrogen; R⁷ is acetyl; R¹⁶ and R¹⁷ are the same as or different from each other and each represents hydrogen or hydroxy; R^21a and R^21b are bound together with oxygen, or either one of them represents hydroxy and the other is hydrogen; and R¹² represents methyl or -CH₂OH. In yet another embodiment of the compound according to formula 21, R^{3 "}, R^{6 "}, R⁷ , R¹⁷, R²⁰ and R^21a are hydrogen; R¹⁶ and R^21b are hydroxy; and R¹² is methyl. In another embodiment of a compound according to formula 21, R³ , R⁶ , R⁷ , R¹⁶, R¹⁷ and R^21a are hydrogen; R and R are hydroxy; and R is methyl. In other embodiments of the compound according to formula 21, R^3", R^6", R^7", R¹⁶, R¹⁷ and R^21a are hydrogen; R^21b is hydroxy; and R¹² is methyl. In another embodiment of a compound according to formula 21, R^3", R^6", R¹⁶, R¹⁷ and R^21a are hydrogen; R²⁰ and R^21b are hydroxy; R^7" is acetyl; and R¹² is methyl. In other embodiments of the compound according to formula 21, R^3", R^{6 "}, R¹⁷, R²⁰ and R^21a are hydrogen; R¹⁶ and R^21b are hydroxy; R⁷ is acetyl; and R¹² is methyl. In another embodiment of a compound according to formula 21, R³ , R^{6 '}, R¹⁶, R¹⁷ and R²⁰ are hydrogen; R^21a and R^21b are bound together with oxygen; R⁷ is acetyl; and R¹² is methyl. In yet another embodiment of a compound according to formula 21, R^3", R^6", R¹⁶, R¹⁷, R²⁰ and R^21a are hydrogen; R^{2 lb} is hydroxy; R⁷ is acetyl; and R¹² is methyl. The macrolide compounds of the invention contains asymmetric carbon atoms and, thus, is capable of existing as an enantiomer. The present invention embraces any enantiomeric form of a compound according to formulae 1-21 or HI-HXI, including the racemates or racemic mixtures. In some cases, there may be advantages (i.e., the compound may have greater efficacy), to using a particular enantiomer when compared to the other enantiomer or the racemate or racemic mixture in the methods of the instant invention and such advantages can be readily determined by those skilled in the art. The macrolide compositions of the invention are used as immunosuppression agents in organ or tissue transplantation. As used herein, "immunosuppression agent" refers to an agent whose action on the immune system leads to the immediate or delayed reduction of the activity of at least one pathway involved in an immune response, whether this response is naturally occurring or artificially triggered, whether this response takes place as part of the innate immune system, the adaptive immune system, or both. These immunosuppressive macrolide compositions are administered to a subject prior to, during and/or after organ or tissue transplantation. For example, the macrolide compositions of the invention are used to treat or prevent rejection after organ or tissue transplantation. In one embodiment, these immunosuppressive macrolide compositions are administered in combination with any of a variety of known anti-inflammatory and/or immunosuppressive compounds. Suitable anti-inflammatory and/or immunosuppressive compounds for use with the macrolide compounds of the invention include, but are not limited to, methotrexate, cyclosporin A (including, for example, cyclosporin microemulsion), tacrolimus, corticosteroids and statins. The macrolide compositions of the invention are also used to treat or alleviate a symptom associated with an immune-related disorder, such as, for example, an autoimmune disease or an inflammatory disorder. The compositions include a pharmaceutically acceptable carrier and a compound according to formulae 1-21 or HI-HXI, or pharmaceutically acceptable salts or hydrates thereof. Autoimmune diseases include, for example, Acquired Immunodeficiency Syndrome (AIDS, which is a viral disease with an autoimmune component), alopecia areata, ankylosing spondylitis, antiphospholipid syndrome, autoimmune Addison's disease, autoimmune hemolytic anemia, autoimmune hepatitis, autoimmune inner ear disease (AIED), autoimmune lymphoproliferative syndrome (ALPS), autoimmune thrombocytopenic purpura (ATP), Behcet's disease, cardiomyopathy, celiac sprue-dermatitis hepetiformis; chronic fatigue immune dysfunction syndrome (CFIDS), chronic inflammatory demyelinating polyneuropathy (CIPD), cicatricial pemphigoid, cold agglutinin disease, crest syndrome, Crohn's disease, Degos' disease, dermatomyositis-juvenile, discoid lupus, essential mixed cryoglobulinemia, fibromyalgia-fibromyositis, Graves' disease, Guillain-Barre syndrome, Hashimoto's thyroiditis, idiopathic pulmonary fibrosis, idiopathic thrombocytopenia purpura (ITP), IgA nephropathy, insulin-dependent diabetes mellitus, juvenile chronic arthritis (Still's disease), juvenile rheumatoid arthritis, Meniere's disease, mixed connective tissue disease, multiple sclerosis, myasthenia gravis, pernacious anemia, polyarteritis nodosa, polychondritis, polyglandular syndromes, polymyalgia rheumatica, polymyositis and dermatomyositis, primary agammaglobulinemia, primary biliary cirrhosis, psoriasis, psoriatic arthritis, Raynaud's phenomena, Reiter's syndrome, rheumatic fever, rheumatoid arthritis, sarcoidosis, scleroderma (progressive systemic sclerosis (PSS), also known as systemic sclerosis (SS)), Sjogren's syndrome, stiff-man syndrome, systemic lupus erythematosus, Takayasu arteritis, temporal arteritis/giant cell arteritis, ulcerative colitis, uveitis, vitiligo and Wegener's granulomatosis. Inflammatory disorders, include, for example, chronic and acute inflammatory disorders. Examples of inflammatory disorders include Alzheimer's disease, asthma, atopic allergy, allergy, atherosclerosis, bronchial asthma, eczema, glomerulonephritis, graft vs. host disease, hemolytic anemias, osteoarthritis, sepsis, stroke, transplantation of tissue and organs, vasculitis, diabetic retinopathy and ventilator induced lung injury. In one embodiment, the macrolide compositions used to treat an immune-related disorder are administered in combination with any of a variety of known anti-inflammatory and/or immunosuppressive compounds. Suitable known compounds include, but are not limited to methotrexate, cyclosporin A (including, for example, cyclosporin microemulsion), tacrolimus, corticosteroids, statins, interferon beta, Remicade (Infliximab), Enbrel (Etanercept) and Humira (Adalimumab). For example, in the treatment of rheumatoid arthritis, the macrolide compositions of the invention are co-administered with corticosteroids, methotrexate, cyclosporin A, statins, Remicade (Infliximab), Enbrel (Etanercept) and/or Humira (Adalimumab). In the treatment of uveitis, the macrolide compositions are administered in conjunction with, e.g., corticosteroids, methotrexate, cyclosporin A, cyclophosphamide and/or statins. Likewise, patients afflicted with a disease such as Crohn's Disease or psoriasis are treated with a combination of a macrolide composition of the invention and Remicaid (Infliximab), and/or Humira (Adalimumab). Patients with multiple sclerosis receive a combination of a macrolide composition of the invention in combination with, e.g., glatiramer acetate (Copaxone), interferon beta-la (Avonex), interferon beta-la (Rebif), interferon beta-lb (Betaseron or Betaferon), mitoxantrone (Novantrone), dexamethasone (Decadron), methylprednisolone (Depo-Medrol), prednisone (Deltasone) and/or statins. The present invention also provides methods of treating or alleviating a symptom associated with an immune-related disorder or a symptom associated with rejection following organ transplantation. For example, the compositions of the invention are used to treat or alleviate a symptom of any of the autoimmune diseases and inflammatory disorders described herein. Symptoms of an immune-related disorder include, for example, inflammation, fever, loss of appetite, weight loss, abdominal symptoms such as, for example, abdominal pain, diarrhea or constipation, joint pain or aches (arthralgia), fatigue, rash, anemia, extreme sensitivity to cold (Raynaud's phenomenon), muscle weakness, muscle fatigue, changes in skin or tissue tone, shortness of breath or other abnormal breathing patterns, chest pain or constriction of the chest muscles, abnormal heart rate (e.g., elevated or lowered), light sensitivity, blurry or otherwise abnormal vision, and reduced organ function. As described above, the macrolide compositions of the invention are administered alone, or alternatively, in combination with another form of therapy, referred to herein as "combination therapy" (or "co-therapy"). Co-therapy includes the administration of a macrolide composition of the invention and known therapy for a given immune-related disorder, or set of immune-related disorders. For example, a macrolide composition administered as an immunosuppressive agent in the treatment and/or prevention of rejection following organ transplantation is "co-administered" with one or more known immunosuppressive agents, such as, for example cyclosporin A, tacrolimus, and corticosteroids. Macrolide compositions administered in the treatment of an autoimmune disease and/or inflammatory disorder is administered with any of a variety of known therapies. Such therapies include, for example, known immunosuppressive agents such as COX2 inhibitors, corticosteroids, statins, cannabinoids (and derivatives thereof), interferon beta, aspirin and other anti-inflammatory agents, inhibitors of tumor necrosis factor, and inhibitors of interleukin 1. The beneficial effect of the combination includes, but is not limited to, pharmacokinetic or pharmacodynamic co-action resulting from the combination of therapeutic agents. Administration of these therapeutic agents in combination typically is carried out over a defined time period (usually minutes, hours, days or weeks depending upon the combination selected). "Combination therapy" may, but generally is not, intended to encompass the administration of two or more of these therapeutic agents as part of separate monotherapy regimens that incidentally and arbitrarily result in the combinations of the present invention. "Combination therapy" is intended to embrace administration of these therapeutic agents in a sequential manner, that is, wherein each therapeutic agent is administered at a different time, as well as administration of these therapeutic agents, or at least two of the therapeutic agents, in a substantially simultaneous manner. Substantially simultaneous administration can be accomplished, for example, by administering to the subject a single capsule having a fixed ratio of each therapeutic agent or in multiple, single capsules for each of the therapeutic agents. The therapeutic agents can be administered by the same route or by different routes. For example, a first therapeutic agent of the combination selected may be administered by intravenous injection while the other therapeutic agents of the combination may be administered orally. Alternatively, for example, all therapeutic agents may be administered orally or all therapeutic agents may be administered by intravenous injection. The sequence in which the therapeutic agents are administered is not narrowly critical. "Combination therapy" also can embrace the administration of the therapeutic agents as described above in further combination with other biologically active ingredients and non-drug therapies ( e.g., surgery or radiation treatment.) Where the combination therapy further comprises a non-drug treatment, the non-drug treatment may be conducted at any suitable time so long as a beneficial effect from the co-action of the combination of the therapeutic agents and non-drug treatment is achieved. For example, in appropriate cases, the beneficial effect is still achieved when the non-drug treatment is temporally removed from the administration of the therapeutic agents, perhaps by days or even weeks. To evaluate whether a patient is benefiting from the administration of a macrolide, alone or in combination, one examines the patient's symptoms and/or immune response in a quantitative way, and compares the patient's symptoms and/or immune response before and after treatment with the macrolide compound. For example, a patient's symptom are determined by measuring a particular symptom, or set of symptoms, in a patient before and after treatment with a macrolide composition. For example, one measures and monitors symptoms such as fever, joint pain, muscle weakness using any of the standard measurement techniques known in the art. In a successful treatment, the patient status has improved {i.e., the measurement number has decreased, or the time to sustained progression has increased). A compound that is administered in a pharmaceutical composition is mixed with a suitable carrier or excipient such that a therapeutically effective amount is present in the composition. The term "therapeutically effective amount" refers to an amount of the compound that is necessary to achieve a desired endpoint {e.g., decreasing symptoms associated with an immune-related disorder). A variety of preparations can be used to formulate pharmaceutical compositions containing the macrolide compound, including solid, semi solid, liquid and gaseous forms. Techniques for formulation and administration are found, for example, in "Remington: The Science and Practice of Pharmacy, Twentieth Edition," Lippincott Williams & Wilkins, Philadelphia, PA. Tablets, capsules, pills, powders, granules, dragees, gels, slurries, ointments, solutions suppositories, injections, inhalants and aerosols are examples of such formulations. The formulations are administered in either a local or systemic manner or in a depot or sustained release fashion. Administration of the composition is performed in a variety of ways. Among others, oral, buccal, rectal, parenteral, intraperitoneal, intradermal, transdermal, intranasal, and intratracheal means can be used. The compositions and combination therapies of the invention are administered in combination with a variety of pharmaceutical excipients, including stabilizing agents, carriers and/or encapsulation formulations as described herein. The preparation of pharmaceutical or pharmacological compositions will be known to those of skill in the art in light of the present disclosure. Typically, such compositions are prepared as injectables, either as liquid solutions or suspensions; solid forms suitable for solution in, or suspension in, liquid prior to injection; as tablets or other solids for oral administration; as time release capsules; or in any other form currently used, including creams, lotions, mouthwashes, inhalants and the like. For human administration, preparations should meet sterility, pyrogenicity, general safety and purity standards as required by FDA Office of Biologies standards. Administration of compounds alone or in combination therapies are, e.g., intralesional, intraperitoneal, intramuscular or intravenous injection; infusion; or topical, nasal, oral, ocular or otic delivery. A particularly convenient frequency for the administration of the compounds of the invention is once a day. Upon formulation, therapeutics are administered in a manner compatible with the dosage formulation, and in such amount as is pharmacologically effective. The formulations are easily administered in a variety of dosage forms, such as the injectable solutions described, but drug release capsules and the like can also be employed. In this context, the quantity of active ingredient and volume of composition to be administered depends on the host animal to be treated. Precise amounts of active compound required for administration depend on the judgment of the practitioner and are peculiar to each individual. A minimal volume of a composition required to disperse the active compounds is typically utilized. Suitable regimes for administration are also variable, but are typified by initially administering the compound and monitoring the results and then giving further controlled doses at further intervals. For example, for parenteral administration, a suitably buffered, and if necessary, isotonic aqueous solution is prepared and used for intravenous, intramuscular, subcutaneous or even intraperitoneal administration. One dosage is dissolved in 1 ml of isotonic NaCl solution and either added to 1000 ml of hypodermolysis fluid or injected at the proposed site of infusion, (see for example, "Remington: The Science and Practice of Pharmacy, Twentieth Edition," Lippincott Williams & Wilkins, Philadelphia, PA). A carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), suitable mixtures thereof, and vegetable oils. The proper fluidity can be maintained, for example, by the use of a coating, such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants. The prevention of the action of microorganisms can be brought about by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like. In many cases, it will be preferable to include isotonic agents, for example, sugars or sodium chloride. Prolonged absorption of the injectable compositions can be brought about by the use in the compositions of agents delaying absorption, for example, aluminum monostearate and gelatin. In some embodiments, compositions of the invention are formulated for parenteral administration, e.g., formulated for injection via the intravenous, intramuscular, subcutaneous, intralesional, or even intraperitoneal routes. The preparation of a composition that contains a compound or combination therapy of the invention, or an active component or ingredient will be known to those of skill in the art in light of the present disclosure. Typically, such compositions can be prepared as injectables, either as liquid solutions or suspensions; solid forms suitable for using to prepare solutions or suspensions upon the addition of a liquid prior to injection can also be prepared; and the preparations can also be emulsified. Suitable preservatives for use in solution include benzalkonium chloride, benzethonium chloride, chlorobutanol, thimerosal and the like. Suitable buffers include boric acid, sodium and potassium bicarbonate, sodium and potassium borates, sodium and potassium carbonate, sodium acetate, sodium biphosphate and the like, in amounts sufficient to maintain the pH at between about pH 6 and pH 8, and preferably, between about pH 7 and pH 7.5. Suitable tonicity agents are dextran 40, dextran 70, dextrose, glycerin, potassium chloride, propylene glycol, sodium chloride, and the like, such that the sodium chloride equivalent of the ophthalmic solution is in the range 0.9 plus or minus 0.2%. Suitable antioxidants and stabilizers include sodium bisulfite, sodium metabisulfϊte, sodium thiosulfite, thiourea and the like. Suitable wetting and clarifying agents include polysorbate 80, polysorbate 20, poloxamer 282 and tyloxapol. Suitable viscosity-increasing agents include dextran 40, dextran 70, gelatin, glycerin, hydroxyethylcellulose, hydroxmethylpropylcellulose, lanolin, methylcellulose, petrolatum, polyethylene glycol, polyvinyl alcohol, polyvinylpyrrolidone, carboxymethylcellulose and the like. The compounds of the invention can be formulated by dissolving, suspending or emulsifying in an aqueous or nonaqueous solvent. Vegetable {e.g., sesame oil, peanut oil) or similar oils, synthetic aliphatic acid glycerides, esters of higher aliphatic acids and propylene glycol are examples of nonaqueous solvents. Aqueous solutions such as Hank's solution, Ringer's solution or physiological saline buffer can also be used. In all cases the form must be sterile and must be fluid to the extent that easy syringability exists. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms, such as bacteria and fungi. Solutions of active compounds as free base or pharmacologically acceptable salts can be prepared in water suitably mixed with a surfactant, such as hydroxypropylcellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof and in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms. Sterile injectable solutions are prepared by incorporating the active compounds in the required amount in the appropriate solvent with various of the other ingredients enumerated above, as required, followed by filtered sterilization. Generally, dispersions are prepared by incorporating the various sterilized active ingredients into a sterile vehicle which contains the basic dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, the preferred methods of preparation are vacuum-drying and freeze-drying techniques which yield a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof. For parenteral administration in an aqueous solution, for example, the solution should be suitably buffered if necessary and the liquid diluent first rendered isotonic with sufficient saline or glucose. These particular aqueous solutions are especially suitable for intravenous, intramuscular, subcutaneous and intraperitoneal administration. In this connection, sterile aqueous media which can be employed will be known to those of skill in the art in light of the present disclosure. The preparation of more, or highly, concentrated solutions for intramuscular injection is also contemplated. In this regard, the use of DMSO as solvent is preferred as this will result in extremely rapid penetration, delivering high concentrations of the active compound(s) or agent(s) to a small area. Where the composition or combination therapy is given orally, it can be formulated through combination with pharmaceutically acceptable carriers that are well known in the art. The carriers enable the compound to be formulated, for example, as a tablet, pill, capsule, solution, suspension, sustained release formulation; powder, liquid or gel for oral ingestion by the patient. Oral use formulations can be obtained in a variety of ways, including mixing the compound with a solid excipient, optionally grinding the resulting mixture, adding suitable auxiliaries and processing the granule mixture. The following list includes examples of excipients that can be used in an oral formulation: sugars such as lactose, sucrose, mannitol or sorbitol; cellulose preparations such as maize starch, wheat starch, potato starch, gelatin, gum tragacanth, methyl cellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose and polyvinylpyrrolidone (PVP). Oral formulations include such normally employed excipients as, for example, pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharine, cellulose, magnesium carbonate and the like. In certain defined embodiments, oral pharmaceutical compositions will comprise an inert diluent or assimilable edible carrier, or they may be enclosed in hard or soft shell gelatin capsule, or they may be compressed into tablets, or they may be incorporated directly with the food of the diet. For oral therapeutic administration, the active compounds may be incorporated with excipients and used in the form of ingestible tablets, buccal tables, troches, capsules, elixirs, suspensions, syrups, wafers, and the like. Such compositions and preparations should contain at least 0.1 % of active compound. The percentage of the compositions and preparations may, of course, be varied and may conveniently be between about 2 to about 75% of the weight of the unit, or preferably between 25-60%. The amount of active compounds in such therapeutically useful compositions is such that a suitable dosage will be obtained. The tablets, troches, pills, capsules and the like may also contain the following: a binder, as gum tragacanth, acacia, cornstarch, or gelatin; excipients, such as dicalcium phosphate; a disintegrating agent, such as corn starch, potato starch, alginic acid and the like; a lubricant, such as magnesium stearate; and a sweetening agent, such as sucrose, lactose or saccharin may be added or a flavoring agent, such as peppermint, oil of wintergreen, or cherry flavoring. When the dosage unit form is a capsule, it may contain, in addition to materials of the above type, a liquid carrier. Various other materials may be present as coatings or to otherwise modify the physical form of the dosage unit. For instance, tablets, pills, or capsules may be coated with shellac, sugar or both. A syrup of elixir may contain the active compounds sucrose as a sweetening agent methyl and propylparabensas preservatives, a dye and flavoring, such as cherry or orange flavor. The compositions of the present invention can also be delivered in an aerosol spray preparation from a pressurized pack, a nebulizer or from a dry powder inhaler. Suitable propellants that can be used in a nebulizer include, for example, dichlorodifluoro-methane, trichlorofluoromethane, dichlorotetrafluoroethane and carbon dioxide. The dosage can be determined by providing a valve to deliver a regulated amount of the compound in the case of a pressurized aerosol. Compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable, aqueous or organic solvents, or mixtures thereof, and powders. The liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as set out above. Preferably the compositions are administered by the oral or nasal respiratory route for local or systemic effect. Compositions in preferably sterile ^' pharmaceutically acceptable solvents may be nebulized by use of inert gases. Nebulized solutions may be breathed directly from the nebulizing device or the nebulizing device may be attached to a face mask, tent or intermittent positive pressure breathing machine. Solution, suspension or powder compositions may be administered, preferably orally or nasally, from devices which deliver the formulation in an appropriate manner. Additional formulations suitable for other modes of administration include suppositories. For suppositories, traditional binders and carriers may include, for example, polyalkylene glycols or triglycerides; such suppositories may be formed from mixtures containing the active ingredient in the range of 0.5% to 10%, preferably l%-2%. The subject treated by the methods of the invention is a mammal, more preferably a human. The following properties or applications of these methods will essentially be described for humans although they may also be applied to non-human mammals, e.g., apes, monkeys, dogs, mice, etc. The invention therefore can also be used in a veterinarian context. Pharmaceutical compositions of the present invention contain a therapeutically effective amount of the macrolide compound. The amount of the compound will depend on the patient being treated. The patient' s weight, severity of illness, manner of administration and judgment of the prescribing physician should be taken into account in deciding the proper amount. The determination of a therapeutically effective amount of a macrolide compound is well within the capabilities of one with skill in the art. Although a therapeutically effective amount of a macrolide compound will vary according to the patient being treated, suitable doses will typically include between about 0.1 mg and 1000 mg of the compound. Preferably, a dose contains between about 0.1 mg and 500 mg of the compound. More preferably, a dose contains between about 0.1 mg and 250 mg of the compound. In some cases, it may be necessary to use dosages outside of the stated ranges to treat a patient. Those cases will be apparent to the prescribing physician. Where it is necessary, a physician will also know how and when to interrupt, adjust or terminate treatment in conjunction with a response of a particular patient. The invention will be further described in the following examples, which do not limit the scope of the invention described in the claims. Other Embodiments

While the invention has been described in conjunction with the detailed description thereof, the foregoing description is intended to illustrate and not limit the scope of the invention, which is defined by the scope of the appended claims. Other aspects, advantages, and modifications are within the scope of the following claims.

Claims

What is claimed is:

1. A method of treating an immune-related disorder comprising administering to a patient in need of such treatment a composition comprising a carrier and a non-toxic therapeutically effective amount of a macrolide compound, wherein the macrolide compound is a macrolide compound according to formulae 1-21 or HI-HXI or a pharmaceutically acceptable salt or hydrate thereof.

2. The method of claim 1 , wherein the immune-related disorder is an autoimmune disease selected from the group consisting of a connective tissue disease, a neuromuscular disease, an endocrine disease, a gastrointestinal disease, an autoimmune skin disease, a vasculitis syndrome, a hematologic autoimmune disease, and uveitis.

3. The method of claim 1 , wherein the autoimmune disease is selected from the group consisting of systemic lupus erythematosus (SLE), systemic sclerosis (scleroderma), Sjogren's syndrome, multiple sclerosis (MS), myasthenis gravis, Guillain-Barre syndrome, Hashimoto's thyroiditis, Graves' disease, insulin-dependent (Type 1) diabetes, inflammatory bowel disease, Crohn's disease, ulcerative colitis, psoriatic arthritis, and uveitis.

4. The method of claim 1 , wherein the immune-related disorder is an inflammatory disorder selected from the group consisting of Alzheimer's disease, asthma, atopic allergy, allergy, bronchial asthma, diabetic retinopathy, eczema, glomerulonephritis, graft vs. host disease, hemolytic anemias , sepsis, stroke, vasculitis, and ventilator induced lung injury.

5. A method of alleviating a symptom associate with an immune-related disorder comprising administering to a patient in need of such treatment a composition comprising a carrier and a non-toxic therapeutically effective amount of a macrolide compound, wherein the macrolide compound is a macrolide compound according to formulae 1-21 or HI-HXI, or a pharmaceutically acceptable salt or hydrate thereof.

6. The method of claim 5, wherein the immune-related disorder is an autoimmune disease selected from the group consisting of a connective tissue disease, a neuromuscular disease, an endocrine disease, a gastrointestinal disease, an autoimmune skin disease, a vasculitis syndrome, a hematologic autoimmune disease, and uveitis.

7. The method of claim 5, wherein the autoimmune disease is selected from the group consisting of systemic lupus erythematosus (SLE), systemic sclerosis (scleroderma), Sjogren's syndrome, multiple sclerosis (MS), myasthenis gravis, Guillain-Barre syndrome, Hashimoto's thyroiditis, Graves' disease, insulin-dependent (Type 1) diabetes, inflammatory bowel disease, Crohn's disease, ulcerative colitis, psoriatic arthritis, and uveitis.

8. The method of claim 5, wherein the immune-related disorder is an inflammatory disorder selected from the group consisting of Alzheimer's disease, asthma, atopic allergy, allergy, bronchial asthma, diabetic retinopathy, eczema, glomerulonephritis, graft vs. host disease, hemolytic anemias , sepsis, stroke, vasculitis, and ventilator induced lung injury.

9. The method of claim 5, wherein the macrolide is a racemic mixture of a macrolide compound according to formulae 1-21 or HI-HXI.

10. The method according to claims 1 or 5, wherein the macrolide is enantiomerically pure form of a macrolide compound according to formulae 1-21 or HI-HXI.

11. The method according to claims 1 or 5, wherein the macrolide is administered in combination with a second agent used to treat immune-related disorders.

12. The method of claim 11 , wherein the second agent used to treat inflammation or immune-related disorders is selected from the group consisting of methotrexate, cyclosporin A, tacrolimus, corticosteroids, statins, interferon beta, nonsteroidal anti-inflammatory drugs (NSAIDs), and the disease-modifying anti-rheumatic drugs (DMARDs).

13. The method of claim 12, wherein the second agent is cyclosporin A, and wherein the cyclosporin A is cyclosporin microemulsion.

14. A method of suppressing an immune response associated with organ or tissue transplantation comprising administering to a patient in need of such treatment a composition comprising a carrier and a non-toxic therapeutically effective amount of a macrolide compound, wherein the macrolide compound is a macrolide compound according to formulae 1-21 or HI-HXI or a pharmaceutically acceptable salt or hydrate thereof.

15. The method of claim 14, wherein the macrolide is administered in combination with a second agent used to suppress an immune response associated with organ or tissue transplantation.

16. The method of claim 14, wherein the second agent used to suppress an immune response associated with organ or tissue transplantation is selected from the group consisting of methotrexate, cyclosporin A, cyclosporin microemulsion, tacrolimuscorticosteroids and statins.

17. The method of claim 16, wherein the second agent is cyclosporin A, and wherein the cyclosporin A is cyclosporin microemulsion.

18. The method of claim 14, wherein the macrolide is an enantiomerically pure form of a macrolide compound according to formulae 1-21 or HI-HXI.

19. The method of claim 14, wherein the macrolide is administered to said patient at a time selected from the group consisting of prior to said organ or tissue transplantation, during said organ or tissue transplantation, after said organ or tissue transplantation, and combinations thereof.