JPS5829710A - Remedy for osteoporosis by prostaglandins - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to novel methods of using known agents for the treatment and prevention of diseases of the body and teeth in humans and animals.

The present invention also relates to the use of these known agents to increase the rate of bone healing in conditions such as fractures, bone grafts, etc.

Medical research has shown that many metabolic bone diseases (especially adult bone diseases such as osteoporosis proper)
It has recently been discovered that bone loss results from disturbances in the mechanisms governing the bone replacement process (bone modeling and/or remodeling).

The bone replacement process contributes to the formation and subsequent maintenance of M-grade mechanical ability. These processes are carried out by the combined and integrated activity of two continuously renewing cell numbers, initiated following a stimulus or "activation" that results in the proliferation and differentiation of these cells. be done.

These cells are osteoblasts and osteoclasts, which have complementary but opposite activities. Osteoblasts are cells that perform the function of bone formation, and are cells that perform the functions of bone absorption and removal.They function together with osteoclasts in animals.

The defects in the bone replacement mechanism that lead to anterior foramina differ between young and adult patients. Growth and modeling receive one stroke in young people, while remodeling (and to some extent modeling) receives one chopstick in adults. Young people also experience defects in the expected skeletal bone accumulation, whereas adults have CJ 4 degree bone tissue defects. The subsequent accumulation of bone tissue during the growth period, which remains symptomatic during youth, can predispose adults to develop protovenia or osteovenia.

The following definitions will help you understand the book @ Ming.

(a) "Osteovenia" is a skeletal state of mammals characterized by a reduced volume of the mineralized skeleton 1.

(b) Pre-osteovenia is a skeletal condition characterized by a decrease in overall bone volume.

(Thus, the distinction between total bone volume and mineralized bone volume is important in the discussion of disease and its etiology.
It is also an important committee to evaluate the effectiveness of treatment. For example, Z, F, G, Jaworsugi - ``Physiology and Pathology Off Bone Remodeling''
See the Symposium 12 (1981) on Poly4-L Syndrome in American Orthopedic Clinic. ) (o) "Growth in the 1-meter direction" refers to the increase in bone length due to the ossification process within the cartilage.

(d) "Epiphytic growth 1" (as it remains in the skeleton after paralysis and congenital diseases), when acting alone, produces a uniform increase in the diameter of all 14 pores. Basically, it refers to the growth process that produces a #1-shaped diaphyseal cross section.

(θ)1-modeling” refers to the process of bone activation followed by resorption at one bone location and simultaneous activation of bone formation at another bone location. The modeling process promotes the diameter of some sections over others in response to the biochemical demands acting on the bone. The modeling activity is an irregular cross-section with a zone of varying cortex, SAi; of the general direction of the entire bone, such as that commonly found in the clavicle, ribs, frame bones, etc. produce a curve.

(f) +J modeling refers to bone activation followed by resorption followed by new bone formation temporally at the same bone location in the order IS. The remodeling process produces gradual but gradual changes in the periosteal envelope over the adult lifespan, resulting in moderate changes in bone phase, which are resorbed and replaced by the membrane surface. This results in widening.

Canalamia is a common condition in animals, and especially in adult humans, and is characterized by 44.7 p'J
2) or reduce both bone magnetism of hydroxyapatite. Canalamia typically results in a number of symptomatic manifestations, including back pain, large spontaneous fractures, Colles' fractures, and deformity of the spine. The bones of suffering animals become brittle and this increases the likelihood of fractures occurring. Various types of canal pore diseases are known. For example, Merck manual 1
3rd edition, 1365-1366 (1977) and Dorland's Illustrated Medical Dictionary, 24th edition, W. Saladers Company.
See (1965).

Canal canal disease can be classified in many ways. One way to classify it is by where it occurs in life. In this classification system, the following ridge H1 canalamia exists.

■Congenital. Here, move 9. This was born at a time when there was basically no ability to accumulate skeleton wax at the necessary speed and capacity to meet the longitudinal demands imposed on the skeleton. An example of this condition is called osteogenesis imperfecta.

2. Anything related to growth. Here, animals develop a growing skeleton that accumulates less bone than a normal growing skeleton during immaturity, resulting in individuals with less than the normal amount of bone tissue. There are changes in bone formation, resorption, growth, modeling and remodeling processes. These canals are usually characterized by an almost normal periosteal diameter in the middle relative to their length, but the dorsal medullary cavity is relatively enlarged and has a smaller than normal periosteal diameter. Asthma I, 77=t
I'm using the x' club and making fun of my friends.

Examples of this ridge are secondary to biliary strictures, burrows, joint curvature (secondary to paralysis due to grey-white), muscular dystrophy, and pre-existing hematopoietic diseases. This is a type of stomata disease, and these symptoms are acquired stomata disease (described later).
Although it is similar in pathogenesis to , it occurs in the immature skeleton.

3. Acquired canal pore disease. There are many types of 41ff, both symptomatic and asymptomatic, and the causes of these diseases are not fully understood. Examples of this type of canal disease are senile canal disease,
Suspension after cessation of menstruation, Cushing's perforation, mast cell disease, thyrotoxicosis, secondary parathyroid function phosphatosis, true phthisis (Tru@Disus・Ostsoporosl)
g), including post-traumatic osteodystrophy, and barndoor acromegaly.

Another way to differentiate canalamia is through changes in bone function. The following classifications exist under this classification:

1. Canalamia, characterized by a reduced bone replacement rate. This includes reduced activation, absorption and formation rates. Examples of this type of canal disease are senile canal disease, post-menstrual canal disease, Cushing's canal disease, muscular dystrophy, and true canal canal disease (Tru Di@uII@Ogt*op).
orogig), barnyard acromegaly, chronic renal failure, and estrogen therapy. The first five canalisms are irreversible and primarily affect the endosteal surface. Burnt-aud macroacrosis also cannot be reversed naturally and primarily affects the endosteal and periosteal surfaces.

Little is known about estrogen therapy, which naturally reverses classic kidney failure. There are no known or proven clues to any of these canal diseases, and data on estrogen therapy are incomplete.

2. Canalamia, characterized by an increased rate of bone replacement. Examples of these types of canal diseases are thyrotoxicosis (which is surgically reversible and primarily affects the periosteal, haversian, and endosteal surfaces), and osteogenesis imperfecta (which is naturally occurring). post-traumatic osteodystrophy (which is reversible and primarily affects the periosteal, Haversian and endosteal surfaces) and post-traumatic osteodystrophy (which is reversible on its own and primarily affects the periosteal, Haversian and endosteal surfaces). ) j3. Normal or variable bone replacement rate. Examples of this condition include mass cell disease (and similar conditions including neoplasia), electropathy, and hyperparathyroidism. The first two symptoms do not revert spontaneously and primarily affect the endosteal surface. AJI dermoid hyperfunction primarily affects the periosteal, Haversian, and endosteal surfaces. The reversibility of these symptoms varies.

The methods of the invention are useful in treating the bone functional conditions described under 1 and 3 above.

Factors that affect bone replacement include:

1. Endocrine factors. Mesenchymal cell activation and therefore remodeling rates are consistently increased in acromegaly and thyrotoxicosis, whereas they are decreased in Cushing's disease and similar syndromes including anti-inflammatory steroid therapy, ovariectomy, menstrual cessation, etc. .

2. Sacrocanal factors. A large local increase in bone glue modeling is always and proportionally related to an increase in tissue perfusion due to blood staining following local tissue injury. Local tissue injuries include fractures, burns of the overlying skin, obvious injuries to underlying deeper tissues, bone or soft tissue surgical procedures, local infections, and the like.

3. Neurological factors. Temporary increases in local nerve modeling occur regularly following trauma, infection, or transection of the major peripheral nerves supplying the local area. Gray-white individuals always have a symmetrical circular cortex due to the lack of significant modeling activity and functional innervation.04, age-related factors. Bone replacement occurs at a greater rate and frequency in young people compared to adults. In the adult human skeleton, bone replacement is trivial and results in serious clinical disease.

5. Mechanical factors. Mechanical loading directly stimulates skeletal replacement, apparently by manipulating microenvironmental factors on the bone surface. For example, long periods of space travel associated with reduced gravity, long periods of rest in bed, etc.

6. Stamp, repair, and/or corrective surgical procedures involving diseased, deformed, and/or transplanted mineralized tissue.

7. - Secondary and/or secondary nutritional factors (e.g. - secondary biliary and alcoholic cirrhosis) and 8. The primary goal of pre-renal dialysis stasis therapy is to increase bone formation and/or Or increasing the amount of bone tissue by decreasing bone resorption.

The prostaglandins used in the present invention are derivatives of brostanic acid. A colloquial system of nomenclature has been devised that classifies prostaglandins according to the substituents on the cyclopentane ring.

See N.N. Nelson's Journal of Medical Chemistry-177911 (1974). Further discussion of prostaglandins can be found in Bergestrom et al.
rmaco1. R@w, 20:1 (1968
) and the citations cited therein.

As used herein, the term prostaglandin r analog refers to compounds that are structurally related to prostaglandins (such as cyclopentane or a closely homologous cycloalkane bonded to adjacent carbon atoms of the ring). Prostaglandins have the characteristic biological properties of prostaglandins (in the sense that they have a pair of side chains). See Bergestrom, cited above. Various structural modifications of prostaglandins are known to produce useful prostaglandin analogs. Many of these structural changes are discussed in the US patents mentioned below.

A large number of anti-osteosis agents, ie reagents proposed for the treatment and prophylaxis of canal ostia, are known in the prior art.

Its important mulberry agents include anabolic steroids, various phosphorus-containing agents, vitamin D and related substances, nistro (dietary tl), geleteroids, fluorides, and parathyroid hormones (P).
TH) and calcitonin. Aromatic carboxylic acids have also been described as useful antiosteoporosis agents.

For a detailed review and discussion of such anti-osteotic agents, see U.S. Pat. No. 4,125,621 or U.S. Pat.
See No. 1668.

Many prostaglandins and their analogs are also known. BGM, in U.S. Patent No. 3,069,322, PG
II: is disclosed in US Pat. No. 3,598,858, and PGM, ester is disclosed in US Pat. No. 3,795,697 and US Pat. No. 3,691,216.

20-Impropylidene compound was released in Japan in 1982-9.
No. 7946. Other prostaglandin analogs are described in the following US patents:

It is well known that several prostaglandins have the ability to stimulate bone resorption in vivo.

D. Zumzien et al. Biochemistry Acta 627; 91-100 (1980)
reported that the production of BGM2 and cyclic AMP increases when physical stress is applied on cultured osteocytes in Herit dishes.

Yanaga et al. reported that prostaglandin 17:801 (1
(June 979) evaluated the effects of PGK on growth-related skeletons of canal stomata. From the data presented it is not possible to determine what effect PG- has on non-growth-related canal diseases. Growth-related canal diseases (e.g. muscular dystrophy, stills).

disease, congenital biliary strictures, and ventricular diseases) in which the growing skeleton subsequently accumulates less bone than a normally growing skeleton and has less than the normal amount of bone tissue. Occurs during immaturity when some symptoms that produce an individual develop. Forest Achem's "Bone"
Remodeling And Deutsch Relationship Tow Metapolis Bone Disease
emodelingan4 ita Re1ation
ship to M@tabolic Bone Di
s@as@s) (see Charles C. Thomas, Banner House (1973).

Several other authors have described the effects of BGM-type prostaglandins on bone growth. For example, Yamasaki et al. [Prostaglandin J as a mediator of bone resorption induced by experimental tooth movement in rats]
, T. Dent, Res., 59 (10):
1635-1642 (October 1980), Tashjian et al.
45-647 (April 1977), Dietrich et al., "Stimulation of bone resorption by prostaglandins", P.
r05t&gllndin vol. 810, A2. 631 pages (August 1975). The first quote is PGIc, and PG
It is disclosed that Ic2 increases bone resorption in rats. The latter two quotes also indicate that prostaglandins are
Discloses that it is a mediator of absorption. Further experiments are conducted in vitro and involve dynamic, complex and complex conditions such as those present in individuals suffering from many of the non-growth-related stomas treated with the methods of the present invention. , the above experiments cannot adequately predict the therapeutic value of the drug when it comes to the treatment of canal stomatia in living systems.

Journal of Pedlatrics 97
: 834 836 and 97: 866-867 (1
Two recent articles in 980) describe proliferative bone changes in infants following long-term infusion of PGE.

U.S. Pat. No. 3,982,016 and its divisional applications U.S. Pat. It is disclosed that U.S. Pat. No. 4,097,601 consists of 2-descarboxy-2-(tetrazol-5-yl)-11-desoxy-16-
It is disclosed that aryl-prostaglandins are useful in increasing bone volume in bone diseases. This latter patent notes that the effects of the synthetic prostaglandins in this package were unexpected in light of the fact that natural prostaglandins are known to increase bone resorption. .

Surprisingly and unexpectedly, a wide range of prostaglandins, both natural and synthetic, have been found to be useful in increasing bone deposition and treating bone diseases.

(Accordingly, the present invention comprises administering to an animal suffering from or susceptible to protomia systemically a compound of formula I effective for the treatment or prevention of protomia. Provided are methods for treating or preventing non-growth-related protomia. In Formula I, N is (1) -00OR, where R1 is (
-) hydrogen, (b) (0, -0,,) alkyl, (c)
(0,-0,.)cycloalkyl, (d) (04-
012) Aralkyl, (·) phenyl optionally substituted with 1.2 or 3 chloro or (a, -a, )alkyl, in the (f) para position, (i) -NH
-00-R,,, (b)-〇〇-Ro, (m,)-o-
oo-R, 4 or (b)-OH-N-NH-00-NH
, (wherein R2m is methyl, phenyl, acetamidophenyl, penzamidophenyl, or cNHT R&:
(g) a pharmaceutically acceptable cation; (3) -1
OH20HN (3)-0014, where L4 is (a) amino of 2-NRH (wherein Rs+ and R52 are 1
s2 (1) Hydrogen, (b) (o, -a, 2) alkyl, ■) (
0,-0,. )′>Chloalkyl, ←→ ('7'
12) Aralkyl, (■) optionally substituted with 1.2 or 3 chloro, (o, -o,)alkyl, hydroxy, carboxy, (02-0,)-alfkidicarbonyl or nitro Phenyl, (b)(0,-〇,)
Carboxyalkyl, (daughter) (a2-a,) carbamoylalkyl, (vin) (o, -os)cyanoalkyl, (b) (C3-06) a7tylalkyl, (
X) (07a,,) pensoylalkyl, optionally containing 1.2.3 chloro, (0, to 0.)alkyl, hydroxy, (0,-a,)-alkoxy, carboxy, (o2 -o5) alfkydicarbonyl, or optionally substituted with nitro, (b)pyridyl, optionally with 1.2 or 3 gi of chloro, (ot a,
) alkyl or optionally substituted with (O,=a,)alkoxy, (xi) (a, -o,)pyridylalkyl, optionally 1.2 or 3 chloro, (
0,-C3) optionally substituted with alkyl 1.
(xui)(C+-0n)hydroxyalkyl, (e))(0,-c4)dihydroxyalkyl, (b)(o
(b) pyrrolidino, piperidino, morpholino, piperazino, hexamethyleneimino, viroline, or 3.4-didehydropiperidinyl with 1 or 2fi (0,
-0,2) cycloamino selected from the group consisting of alkyl optionally substituted, (C)R, is hydrogen or (a, -, a4) alkyl, and "s+ is hydrogen other than υ" but otherwise as defined above -NR,Q
carbonylamino of OR5, (d) Formula% where Rs+ and Rss are as defined in (Q) (e) Formula% is also hydrogen or (a, -a4) alkyl and is the same or different from L2 phyllologically acceptable acid addition groups when 〇H, III, II3, or N is -OH2ML, Its, (f) -oo, R, (g) -OH,OH.

(h)-0ONR,R4, (1)-OH7-NR,R6 or (1)-ooHuso2aH, where M is cis or trans-aH-(IH-(ay, )m-1-(OH
,). -1-(0)12),-,-at,-1-00-
(OH,), -OH,-, Tora:/X -(OH2
)ffi-OH-0H-1-0H-OH(oa, )m
-1"2-1 or -00-(OH2), -oyr, -, L is α-OH:β-uSmam, or oxo, Rs is hydrogen, hydroxy, or methyl, E, is trans-OH-0H-1-0H, -0H2-1 or -〇=0-, Q is α-OH:β-R7, α-R, iβ-OH, or oxo, A, is α-H: β-OH,, α-0H5; β-H; α-
H:β-H1α-P:β-1 or α-0H3:β-〇H
5, and R7 is l) -(OH,)1)-OH,,2) cis-0
H-OH-OH2-OH,,3) -CQH,), -
0miOHs 4) -(OHz)s-on-o(oH
,, )2, or 5) ' (R5R4) (aH,
) goH2R+a, R2 is hydrogen or methyl, R5 and R4 are the same or different and are hydrogen or methyl, R5 and R4 are the same or different and are hydrogen, methyl or ethyl, ``+4 is hydrogen or (a, -04) is alkyl, g is an integer from 1 to 4, horse is an integer from 3 to 5, n is an integer from 5 to 7, p is an integer from 1 to 6, or N, is -0ONR5
5SQ) Pharmacologically acceptable salts thereof when Rs+.

(2) Anabolic steroids, estrous steroids, vitamin D
and its metabolites, phosphorus-containing agents, PTH, inorganic fluoride-containing agents, calcium salts, and calcitonin. in which all variables are as defined above, and the formula is effective to treat or prevent the aforementioned osteoporosis, together with the known anti-osteoporosis agent or agents described above. An improvement consisting in the simultaneous administration of caps consisting of compounds of I.

(B) Anabolic steroids, estrous steroids, vitamin D
1 and its metabolites, phosphorus-containing agents, PTH, inorganic fluoride-containing agents, calcium salts, and calcitonin. in a unit dosage form of a pharmaceutical composition, all variables as defined above, for the treatment or prevention of said protoostasis in combination with said known anti-osteoporosis agent or plurality thereof. An improvement consisting of an amount of a compound of formula 1 that is a unit dose effective to.

(4) an animal exhibiting a fracture comprising systemically administering to the fracture animal an amount effective to increase the rate of healing of a fracture of a prostaglandin of Formula I, with all variables as defined above; A method of increasing the rate of fracture healing.

A method of increasing the rate of successful bone grafting comprising administering systemically to an animal in need of a bone graft.

(6) Systemically administering to an animal suffering from a dental disease an amount of a compound of formula I, in which all variables are as above, effective to enhance alveolar reconstitution and/or healing of the tooth. A method for enhancing the reconstitution and/or healing of alveolar nitrogen to the teeth of said animal, comprising administering the method to said animal.

In achieving the objects of the present invention, useful metal compounds have the formula l
They are prostaglandins and prostaglandin conductors. These compounds significantly increase bone density and enhance the bone replacement rate in dogs under conditions similar to those described in Example 1. Under these conditions, bristaglandins that are as potent as at least 1% PGIt significantly increase bone mass and enhance bone replacement. The term "antiosteoporosis PGM type 2 pro-XJI grandin" is meant to include all such prostaglandins and related compounds. Examples of such compounds are PGICl, 2-decarboxy-2-hydroxy-PGIC.

PGM, , 15 Keto PGM, , 16.16-Cystyl PGM, , 178.20-Dimethyl-6-oxo-PGK% mefl ester, 178.20-Dimethyl-trans-delta-2-PC
I,, PGM, N-methanesulfonylamide, 9-deoxy-9-methylene-16,16-dimethyl-PGE2, (158) -15-methyl-PGIC2, (15R)
-15-methyl-PGI2.11-deoxy-16,
16-cymethyl-PG-111-deoxy-11α-1
6,16-)dimethyl-BGM, 6-oxo-11-deoxy-11α, 16.16-
) Dimethyl-PGE2. 6-oxo-PGI02. 6-oxo-PGM1. 2-decarboxy-2-hydroxymethyl-PGM,
11-deoxy-15-methyl-PGM,,PGIC
, 16,16-difluoro-PGM, and 20-isopropylidene-PGχ.

and alkyl esters, pharmacologically acceptable salts and derivatives thereof.

PGI2 is the most preferred compound of the invention.

Also 15-keto-PGI! t, type compounds, especially 15-
i) -PGM2 and 16.16-dimethy/l/ -P
+7) Stable esters, especially p-(p-acetamidobenzylamide) phenyl ester and α-semicarbasino p-tolyl ester, are also preferred.

Regarding the above divalent substituents (e.g. LI, QI and A,
), these divalent groups are defined as α-R1:lI-mj, where R1 is 0. to o12 represents a substituent on a divalent moiety in the α configuration with respect to the plane of the cyclopentane ring, and Rj represents a substituent on a divalent moiety in the β configuration with respect to the plane of the ring. Therefore, when L is defined as .alpha.-0H:.beta.H, the 8-hydroxy hydroxy is in the .alpha.-configuration and the hydrogen substituent is in the .beta.-configuration.

The carbon atom content of a hydrocarbon-containing moiety of Gods is indicated by a prefix indicating the minimum and maximum number of carbon atoms in that moiety. That is, the prefix (Ot-03) indicates the carbon atom portion of the set tlk1 to wkj.

Therefore, ('j 'B) alkyl is carbon atom Che or 3
Al refers to methyl, ethyl, propyl and isopropyl.

When Q, contains a methyl If substituent, all compounds are named "15-methyl" compounds.

Furthermore, when the 81 moiety contains a hydroxyl group in the I-configuration, it is further named a "15-shrimp" compound. - (OH,), - or -〇 ty O-
The prostaglandin compounds of the present #I therapy containing are therefore referred to as %13,14-dihydro-1 or %13,14-didehydro compounds, respectively.

-(cm,)pO of a straight chain where R7 is defined above with m
Hs, the compounds so written are r 19,20-dinor, "20-nor,""20-methyl" or "20-dinor," respectively, when p is 1.2.4.5. ethyl compound. R7 is branched-0 (R, R4
)-(OH2)g-OH,R,, the compound described as such is ``17--'' when g is 4 or 5.
, 18-, 19-, or 20-alkyl" or [
17,17-, 17,18-, 17,19-, 17,2
0-, 18, 18-.

18.19-, 18.20-, 19.19-, or 19.20-dialkyl" compounds, where the unbranched portion of the chain is at least nibutyl, e.g., when g is 5, "17.20-dimethyl" A compound is described (1
-methylphenyl).

When R is cis-OH=QH-0H20H, the compounds so described are named "cis-17,18-didehydro" compounds.

When R, is -(OH2), -aH=a (OH,)2, the compound so described is named a "20-isopropylidene" compound.

When N, is ~0OL4, the compounds herein are referred to as amides. When N is -00OR, the compounds herein are referred to as prostaglandin esters and salts.

Examples of novel amides (i.e., N is -001a) herein include:

(1) Amides within the range of the seven alkylamide groups of the formula -NR, R, 2 include methyl amide, ethyl amide, n-propyl amide, n-butyl amide, n-pentyl amide, n-hexyl amide, n- Butylamide, n-octylamide, n-7nylamide, n-decylamide, n
-undecylamide, and n-dodecylamide and their isomeric forms. Further examples include dimethylamide, diethylamide, di-n-propylamide, di-n-
butylamide, methylethylamide, methylpropylamide, methylbutyramide, ethylpropylamide, ethylbutyramide, and propylbutyramide.

Amides within the scope of cycloalkylamides include cyclopropylamide, cyclobutyramide, cyclopentylamide, 2,3-dimethylcyclopentylamide, 2,2-
Dimethylcyclopentylamide, 2-methylcyclobentylamide, 3-tert-butylcyclopentylamide, cyclohexylamide, 4-tert-butylcyclohexylamide, 3-isopropylcyclohexylamide, 2.
2-dimethylcyclohexylamide, cycloheptylamide, cyclooctylamide, cyclononylamide, cyclodecylamide, N-methyl-N-cyclobutylamide, N-methyl-N-cyclopentylamide, N-methyl-N-cyclohexylamide , N-ethyl-N-cyclopentylamide, and N-ethyl-N-cyclohexylamide. Amides within the range of aralkylamino (
Mabenzil 7! )", 2-7enyl ethylamide, and [w-methyl-N-benzylamide.t
! The intermediates within the range of converted phenylamides include p-retroroae 1] de-m-chloroanilide, 2,4-dicycloanilide
J-do, 2.4.6-) Lichloroaelide, m-nido-anilide, p-nitroanilide, p-methoxyanilide
]do, 3,4-dimethoxyanilide, 3,4.5- )
Q methoxyanilide, p-hydroxymethylae I]
do, p-methylanilide, m-methylanilide, p-
They are ethylanilide, t-butylanilide, p-carboxyanilide, p-methoxylponylanilide, mercarboxanilide, and O-hydroxyanilide. The common compounds of carboxyalkylamino are carboxyethylamide, carboxypropylamide, carboxymethylamide, and carboxybutyramide.

Amides within the range of carno (moylalkylamino) are carno (moylmethylamide, carbamoylethylamide,
Carno(moylpropylamide), and Carno(moylbutyramide). Amides within the scope of cyanoalkylamino are cyanomethylamide, cyanoethylamide, cyanopropylamide, and cyanobutyramide. Amides within the scope of acetylalkylamino are acetylmethylamide, acetylbutyramide, acetylpropylamide, and acetylbutyramide.Amides within the scope of benzoylalkylamino are benzoylmethylamide, benzoylethylamide, benzoylpropylamide, and dibenzoylbutyramide. Amides within the scope of substituted benzoylalkylamino include p-chlorobenzoylmethylamide, m-chlorobenzoylmethylamide,
2,4-dichlorobenzoylmethylamide, 2,4.6
-) dichlorobenzoylmethylamide, m-nitrobenzoylmethylamide, p-nitrobenzoylmethylamide, p-methoxybenzoylmethylamide, 2,4-
Dimethoxybenzoylmethylamide, 3.4.5-trimethoxybenzoylmethylamide, p-hydroxymethylbenzoylmethylamide, p-methylbenzoylmethyl:amide, m-methylbenzoylmethylamide, p-
Ethylbenzoylmethylamide, t-butylbenzoylmethylamide, p-carboxybenzoylmethylamide, m-methoxycarbonylbenzoylmethylamide, 〇-carboxybenzoylmethylamide, O-hydroxybenzoylmethyl 7miY, p-chlorobenzoylmethylamide , m-chlorobenzoylethylamide, 2.4
-1 chlorobenzoylethylamide, 2.4.6-)
dichlorobenzoylmethylamide, m-nitrobenzoylethylamide, p-nidotetrahenzoylethylamide,
p-methoxybenzoylethylamide, V-methoxybenzoylethylamide, 2,4-dimethoxybenzoylethylamide, 3.4.5-)rimethoxybenzoylethylamide, p-hydroxymethylbenzoylethylamide, p-methylbenzoylethylamide , m-methylbenzoylmethylamide, p-ethylbenzoylethylamide, 7-butylbenzoylmethylamide, p-carboxybenzoylethylamide, m-methoxycarbonylbenzoylethylamide, ρ-carboxybenzoylethylamide, 0-hydroxybenzoylethyl amide, p-chlorobenzoylpropylamide, benzoylpropylamide, 2,4-dichlorobenzoylpropylamide, 2.4゜6-tricyclopenzoylpropylamide, m-nitrobenzoylpropylamide , p~nitrobenzoylp-viramide, p-methoxybenzoylp-viramide, 2.4-dimethoxybenzoylpropylamide, 3.4.5-) dimethoxybenzoylpropylamide, p-hydroxymethylbenzoylpropylamide, P-methyl Benzoylpropylamide, Oboro-methylbenzoylpropylamide, p-ethylbenzoylpropylamide, 1-butylbenzoylpropylamide, p-carboxybenzoylpropylamide, methoxycarbonylbenzoylpropylamide,
0-carboxybenzoylpropylamide, 0-hydroxybenzoylprebylamide, p-chlorobenzoylbutyramide, m-chlorobenzoylbutyramide, 2
,4-dichlorobenzoylbutyramide, 2゜4.6-
) dichlorobenzoylbutyramide, vagina-nitrobenzoylmethylamide, p-nidotetrahenzoylbutyramide, p-methoxybenzoylbutyramide, 2,4-dimethoxybenzoylbutyramide, 3.4.5-)
Dimethoxybenzoylbutyramide, p-hydroxymethylbenzoylbutyramide, p-methylbenzoylbutyramide, m-methylbenzoylbutyramide, p-
Ethylbenzoylbutyramide, m-methylbenzoylbutyramide, p-ethylbenzoylbutyramide, t
-butylbenzoylbutyramide, ν-carpoxybenzoylbutyramide, oboro-methoxycarbonylbenzoylbutyramide, 0-carboxybenzoylbutyramide, and 0- and dorxybenzoylmethylamide.

Amides within the scope of pyridylamino are α-pyridylamide, β-pyridylamide, and r-pyridylamide. Amides within substituted pyridylamino are 4-methyl-
α-pyridylamide, 4-methyl-! -pyridylamide, 4-chloro-α-pyridylamide, and 4-chloro-
β-pyridylamide. Amides within the scope of pyridylalkylamino include α-pyridylmethylamide, β-pyridylmethylamide, r-pyridylmethylamide, α-pyridylmethylamide,
pyridyl ethylamide, l-pyridylmethylamide, r
-pyridylethylamide, α-pyridylpropylamide,! -pyridylpropylamide, r-pyridylpropylamide, σ-pyridylbutyramide, β-pyridylbutyramide, and r-pyridylbutyramide. Amides within the scope of substituted pyridylalkylamides include 4-methyl-d-pyridylmethylamide, 4-methyl-! -pyridylmethylamide, 4-chloro-α-pyridylmethylamide, 4-riW:I stomach-! -pyridylmethylade, 4-
Methyl-α-pyridylpropylamide, 4-methyl-!
- Viridylp is a combination of vilamido, 4-chloro-α-pyridylpropylamide, 4-chloro-β-pyridylpropylamide, 4-methyl-α-pyridylbutyramide, 4-methyl-β-pyridylbutylamino V-hydroxyalkylamino. Amides in the range include hydroxyalkylamide, β-hydroxyethylamide, β-hydroxypropylamide, r-hydroxypropylamide, l-(hydroxymethyl)ethyl-amide, 1-(hydroxymethylbribilamide, (2-hydroxy methyl) propyramide,
and α,α-dimethyl-human p-xyethylamide. Amides in the dihydroxyalkylamino range include dihydroxymethylamide, β, r-dihydroxypropylamide, '1-(hydroxymethyl)2-hydroxymethylacido, β, r-dihydroxybutyramide, β,
δ-dihydroxybutyramide, r,a-dihydroxybutyramide, and 1,1-bis(hydroxymethyl)
It is ethylamide.

Amides in the trihydroxyalkylamino range are tris(hydroxy-methyl)-methylamide and 1,3-dihydroxy-2-hydroxymethylbribilamide.

(2) Amides within the scope of the above cycloamino group include pyrrolidylamide, piperidylamide, morpholinylamide, hexamethyleneiminylamide, piperazinylamide, pyrrolinylamide, and 3,4-didehydropiperidinyl It is an amide.

(3) Amides in the carbonylamino range of 2-NR, , OOR, are methylcarbonylamide, ethylcarbonylamide, phenylcarbonylamide, and benzylcarbonylamide.

(4) Amides within the scope of sulfonylamino of formula -NR, , 5o2R, are methylsulfonylamide, ethylsulfonylamide, phenylsulfonylamide, p-tolylsulfonylamide, benzylsulfonylamide.

Examples of alkyl of 1 to 12 carbon atoms are methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl,
These are isomeric forms.

Contains alkyl-substituted cycloalkyl (a, -a,.

) Examples of cycloalkyl are cyclopropyl, 2-methylcyclopropyl, 2,2-dimethylcyclopropyl, 2.
3-diethylcyclopropyl, 2-butylcyclopropyl, cyclobutyl, 2-methylcyclobutyl, 3-propylcyclobutyl, 2,3.4-triethylcyclobutyl, cyclopentyl, 2,2-dimethylcyclopentyl, 2-pentyl Schif Pentyl, 3-tert-butylcyclopentyl, cyclohexyl, 4-tert-butylcyclohexyl, 3-isopropylcyclohexyl, 2,2-
They are dimethylcyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, and cyclodecyl.

('7'It) Examples of aralkyl are benzyl, 2-phenylethyl, 1-phenylethyl, 2yenylprobyl, 4-phenylbutyl, 3-phenylbutyl, 2
-(i-su7thyl ethyl), and 1-(2-su7thylmethyl).

Examples of phenyl substituted with 1 to 3 chlorop or alkyl of 1 to 4 carbon atoms are p-chlorophenyl, m-chlorophenyl, 2,4-1-chlorophenyl, 2 ,4.6
-)cyclophenyl, p-)lyl, m-)lyl, o
-tolyl, p-ethylphenyl, p-tert-butylphenyl, 215'' methylphenyl, 4-chloro0-2-methylphenyl, and 214-cyclo3-methylphenyl.

Examples of (a,-O,)cycloalkyl optionally substituted with di(o,-a4)alkyl are cyclobutyl, 1
-Propylcyclobutyl, 1-butylcyclobutyl, 1
-Pentylshift tetrabutyl, 2-methylcyclobutyl, 2
-Propylcyclobutyl, 3-ethylcyclobutyl, 3
-propylcyclobutyl, 2.3.4-) ethylcycloptyl, cyclopentyl, 2.2-dimethylcyclopentyl, 3-ethylcyclopentyl, 3-propylcyclopentyl, 3-butylcyclopentyl, 3-tert-butylcyclopentyl, 1 -methyl-3-propylcyclopentyl, 2-methyl-3-propylcyclopentyl,
2-Methyl-4-propylcyclopentyl, cyclohexyl, 3-ethylcyclohexyl, 3-isopropylcyclohexyl, 4-methylcyclohexyl, 4-ethylcyclohexyl, 4-propylcyclohexyl, 4-butylcyclohexyl, 4-tert-butylcyclohexyl, 2 6-dimethylcyclohexyl, 2,2-dimethylcyclopropyl, 2,6-dimethyl-4-propylcyclohexyl, and cycloheptyl.

Pharmacologically acceptable cations within R include pharmacologically acceptable gold-14m ions, ammonium, amine cations, or quaternary ammonium cations.

Particularly preferred gold F4 cations are those from alkali metals such as lithium, sodium, and potassium, alkaline earth metals such as magnesium and calcium, but others such as aluminum, zinc, and iron. The cationic form of the metal is within the scope of this invention.

Pharmacologically acceptable amine cations are those derived from primary, secondary or tertiary amines. Examples of suitable amines are methylamine, diethylamine, triethylamine, ethylamine, dibutylamine, triisodeolamine, N-methylhexylamine, decylamine, dodecylamine, allylamine, stomach thylamine, cyclopentylamine, dicyclohexylamine, benzylamine, Aliphatic, cycloaliphatic, and araliphatic amines having up to about 18 carbon atoms, such as dibenzylamine, α-phenylethylamine, β-phenylethylamine, ethylenediamine, diethylenetriamine, and hetero Cyclic amines such as piperidine, morpholine, pyrrolidine, piperazine and their lower alkyl derivatives such as 1-methylpiperidine, 4
-ethyl%, holin, 1-isopropylpyrrolidine, 2
-Methylpimaricin, 1,4-dimethylpiperazine, 2
-methylpiperidine, etc., as well as amines with water-solubilizing or parent groups, such as mono-, di- and triethanolamine, ethyljetanolamine, y-butylethanolamine, 2-amino-1-butanol, 2-amino- 2-ethyl-1,3-propanediol, 2-amino-2-methyl-1-propanol, tris(human tetraxymethyl)amino, +rtan, IJ-phenylethanolamine, N-(p-tert-amyl phenyl)-jetanolamine, glactamine, N-methylpyridine, N
- Methylglufusamine, ephedrine, phenylnibulin, epinephrine, brocaine, and others. Further useful amine salts are basic amino acid salts such as lysine and arginine.

Suitable pharmacologically acceptable quaternary ammonium cations include tetramethylammonium, tetraethylammonium, benzyltrimethylammonium, phenyltriethylammonium, and the like.

Prostaglandins within the scope of the present invention are known and can be synthesized by methods described in the US patents mentioned above.

Although the invention relates to the treatment of animals, mammals and domestic birds also represent particularly preferred embodiments of the invention. Most preferred is to treat humans according to the invention. The present invention is suitable for humans and other species such as cattle, birds, dogs, cats, and chickens, turkeys, geese, and other birds. Provides a method for treating both domestic and domestic animals.

In the prophylactic use of these antiosteoporous prostaglandins, efficacy in preventing proforamia is determined by patient or animal response, as discussed below for therapeutic use. and are generally somewhat lower than the doses required to treat protomia.

The use of healthy medical prophylaxis requires that prophylactic prostaglandins be used prophylactically only if the animal or patient is particularly susceptible to the development of protoplasia. Conditions and circumstances that increase susceptibility to the above-mentioned protomias are easily discernible to the skilled physician or veterinarian.

The proforamia that is stopped or prevented in accordance with the present invention includes each of the various conditions or symptoms listed above whose long-term effects on the animal are undesirable, and therefore the condition or symptom may be due to direct or indirect disease. related to process.

The methods of the invention are used to increase the rate of healing of bone fractures. Fractures can be the result of the foramina mentioned above, or they can also result from physical injuries that occur to otherwise healthy individuals in everyday life (e.g. sports injuries, injuries from slips and falls). , car accidents, etc.). The inventive method is therefore useful in treating fractures, no matter how they occur.

The utility and principles of the proposed treatment for fractures, including delayed union, also apply to its utility with respect to reconstructive surgical procedures (eg bone grafts and dental procedures).

Low bone replacement rates and inadequate skeletal responses to biochemical stimuli result in inadequate bone quality and laxity, and delayed repair of micro-damages.

In these individuals, the mechanisms responsible for bone repair (prevention of microdamage accumulation in normal healthy individuals) are less responsive to stimuli that normally induce bone healing.

Similarly, the inadequate skeletal response to reconstructive procedures (including dental and bone grafts, especially those of the spine) in these individuals results in delayed healing. - #Reagents that can increase the stimulation of repair* (including activation of bone replacement and activation of cells responsible for repair) will result in a sufficient skeletal response to the reduction in skeletal repair required.

All of E are not uncommon conditions encountered in medical or veterinary practice. Therefore, 76 in such a state
Diagnosis can easily be made by a skilled general physician or veterinarian.

Although any convenient route of administration may be used, oral formulation and administration are preferred. The choice of route of administration is within the skill of the ordinarily skilled veterinarian or physician.

The specifics regarding the prostaglandin used depend on the species, age, weight, sex, and medical condition of the mammal, the severity and length of the proforamia, and the specific antibiotics administered. Osteoporosis is selected according to a variety of factors, including prostaglandins. Following diagnosis of precancerous or bone fracture, an ordinarily skilled physician or veterinarian will readily determine and prescribe an effective amount of an anti-osteoplasty prostaglandin to treat the condition.

In doing so, the physician or veterinarian may use a relatively low dose of the compound in treating, for example, protomia, and subsequently increase the dose until a maximal response is obtained. Such a response is obtained when the total amount of bone stops disappearing and begins to increase.

Thus, a physician or veterinarian may start with a relatively low dose of an anti-osteoporosis prostaglandin by one method. For example, for oral administration of PGIt, he is approximately 0.1~/ky
/day to about 0.2 to /ky-7 days and observe the human or animal patient's response for several weeks. Adjust the prostaglandin dosage up or down until the optimal effective dosage is found. For example, the maximum required dose is usually 1
0 W1iI/ky/F3, although it may occasionally be necessary to exceed these doses if the protomia is particularly severe. Once the minimum effective dose of a particular prostaglandin has been determined for a particular subject, a dosing regimen that will provide that subject with a substantially uniform level of anti-osteotic prostaglandin throughout the system can be established. It is advantageous to give. Therefore, when oral administration is used, it is preferred to use 0.1 to 0.4 yv/kt/day of the antiosteoporotic prostaglandin of the method of the invention. 0.
1 to 0.2/D/day is most preferred. Equivalent dosages of other routes of administration may also be used. Comparable dosage ranges are also used for other anti-osteoporotic prostaglandins based on their efficacy with PGM in the test system described in Example 2.

The use of sound medical therapy requires that prostaglandins be used prophylactically only when the animal or patient is particularly susceptible to the development of protomia. Conditions and circumstances that increase susceptibility to protomia are readily ascertainable to the ordinarily skilled physician or veterinarian and include the factors mentioned above.

The use of anti-osteoporosis prostaglandins is made in conjunction with other forms of conventional therapy for osteoporosis, by further embodying the invention. Other forms of such conventional therapy include, for example, the various chemotherapies described in US Pat. No. 4,125,612. When such combination therapy is used, significant anti-osteotic effects are often obtained with lower effective doses of the compounds used in this invention.

Further embodiments of the present invention provide novel pharmaceutical compositions for antiosteoporosis therapy.

These novel compositions consist of a combination of two or more reagents, one such reagent being an antiosteoporosis prostaglandin, and a second and further reagent being an antiosteoporosis prostaglandin. It is a hitherto known reagent for the treatment of poriatic symptoms. Such previously known antiosteolytic agents include anabolic steroids, estrous steroids, calcium salts,
Inorganic fluorides and calcitonin from a variety of sources are included. Such novel compositions can be advantageously used to stop phlegmonism and are often more effective than would be required if it were the only therapy for the treatment or prevention of phlegmonia. This allows for a reduced dosage of the anti-osteotic prostaglandin of the invention.

In these new pharmaceutical compositions, each unit dose of the prostaglandin of the present invention is used in an amount up to no less than 50% of the amount of the compound in monotherapy. is an amount equal to . Other conventional osteotomy agents or agents thereof are present therein in known amounts for use in the treatment of osteotomia.

The method of the present invention is an improvement over existing methods of treating protomia. The most routinely used treatment methods simply attempt to slow the rate of bone loss in proforamia. The method of the present invention actually increases the total bone mass and replacement position present and therefore represents an advance over the prior art.

Surprisingly and unexpectedly, oral administration of PGI112-type compounds as in Example 2 is more convenient;
is more controlled and produces a better type of bone than the intravenous use of PGII: , which is disclosed in Example 1. Thus, administration of both PGIC and PGI112 produces an increase in bone replacement and results in periosteal hyperostosis in a dose-related pattern, whereas PGI,
The effects on bone of PGM were after 90 days of oral administration, rather than 30 days of intravenous administration as in the case of PGM. Orally administered cucumber clearly facilitates therapeutic use better. ! subperiosteal, PGM.

The new bone obtained with PGE is laminar in nature compared to the newly woven subperiosteal bone obtained with PGE (consisting primarily of fibrous and lamellar bone with interspersed bone bones). ). Additionally, the increase in remodeling activity after administration of PGII was profound and resulted in some cortical porosity, whereas PGIC2 increased remodeling intensity and activity without creating overt porosity. Comparatively, PGI2 is a potent activator of bone remodeling and new bone formation;
It has no obvious adverse effects (at least at the doses and routes used) compared to M, and has the potential to allow better control over bone-induced effects. Also, the new bone, which is laminated in nature after administration of PG, better meets the biochemical needs of the skeleton than woven bone.

This may be an artificial implant or an obvious external (exogenous)
This is the first demonstration of a reagent that can selectively induce new laminated bone in vivo without ingredients. The present invention therefore describes the use of essentially endogenous (versus exogenous, exogenous) reagents alone and with other reagents or procedures in the treatment of bone and related diseases. It provides a combination of therapeutic uses.

The present invention thus provides a powerful activator of bone replacement, allowing potentially selective modulation and modification of bone function, osteocyte function, and osteocyte microenvironment, improving bone quality and Affects both quantity.

The present invention provides a surprising and unexpected method of using drugs previously known to be useful for unrelated pharmaceutical purposes.

The efficacy of prostaglandins and related compositions to treat bone porosity and increase the rate of fracture healing is seen in the examples provided below.

Example 1 The effect of PGM on bone deposition in animals was tested as follows. Four groups of 9-15 month old Peagle dogs were administered various concentrations of PGIC or control by continuous intravenous infusion. Each group of dogs contained two male and two female animals. C 25.80 each for the first three groups
, and 250 ngAt/min (7) pGl.

were administered to each patient. The fourth group received only the diluent, which consisted of 10% ethanol in 0.05 mol Tris solution having a pH of 7.1. The approximate weight range of the animals at the start of the study was 7-13 kF. Animals had free access to water and food.

Control or control was administered by continuous intravenous infusion via the indwelling catheter at the above rates for 30 days. The total fluid volume entering the animal was 8.99 yd/kl per day for 30 days.

Animals were killed at the end of 30 days. BGM for bone changes 25
Gross necropsy was observed for animals receiving 0 and son glkt/min. For animals receiving 250 nv'ky/min, the periosteum appeared rough, thickened, and moist. In cross-section, the original control bone was seen to be surrounded by new bone approximately 3-5I thick. The bone void contained new bone in certain areas. Visible changes, indicative of active bone formation, were evident in the ribs and bones. similar bone deposits 8
It was found in the long bones of the ribs of dogs receiving 0 and 25 ng/ky1 min, but the changes in these animals were lower than that of speciation.

Example 2 Prostaglandin 1 [! 2 orally in gelatin capsules in equal divided doses for 90 days.
, and administered to pegle dogs (4 per sex per group) at doses ranging from 10.0 to 10.0/ky/day. The control group received vehicle (95% ethanol:triacetin).

Clinical signs (loose bowel movements to diarrhea, nausea, injections w>=
<Sclera) commonly associated with prostaglandin administration were observed during the administration period. No skeletal abnormalities were observed. A 1,000 W evaluation of vascular chemistry showed an increase in serum alkaline phosphatase, with no changes in serum calcium and phosphorus, and this increase was also evident in the higher dog group.

Preliminary cortical (femoral and rib) bone evaluation revealed the following: Macroscopically, all (a) intact bones appeared normal at all dose levels; cross-sectional and "ground section" examination showed that the femurs in the high dose (10~/kP/day) group were intact. The diameter was increased by new subperiosteal bone that surrounded the cortical bone (40%l, Q+n). The new bone was densely shiny and very similar to mature lamellar bone. In some areas, the rate of endosteal new bone, the percentage of active formation sites, and the rate of bone gain were all increased in both large and bony bones compared to paired controls.

Under microscopy, new bone under the periosteum was detected at a low dose (1, Omy
lky/day). Compared to controls, the number of concentrated male ligaments and the proportion of active formations of remobling increased in the ribs at low and 11f doses.

Furthermore, the bone growth rate was greater than that of paired controls in both the rib bones of dogs at moderate and low doses, and the femurs of dogs at moderate doses.

Claims (1)

[Claims] 1. Formula [wherein N is (1)-00OR,
1 C (a) hydrogen, (b) (a, -a, 2) alkyl A/
, (c) (0,-0,.)cycloalkyl, (d)
(06-0,2)aralkyl, (,3)1.2 or 3
phenyl optionally substituted with (O, -a,)alkyl, (f) at para position (i) -M
H-GO-R26, (b)-oo-*,,, 匝)-O-
00-R, or α→-0H-N-NH-Co-NH2(
In the formula, R25 is methyl, phenyl, acetamidophenyl, benzamidophenyl, or -NH2i R,, is methyl, phenyl, -MH2 or methoxy; and R54
is phenyl or acetamidophenyl), (g) a pharmaceutically unacceptable cation; (2) -0H20H. 131-00L, where L is (a) an amino of formula -NR51"52, where "51 and R
52 is (1) hydrogen, (b)('l-Cl2)alkyl,
(m) (o, -a,.) cycloalkyl, (to) ('
7'12) aralkyl, (v) optionally 1.2 or 3
chloro, (o, -o, )alkyl, hydroxy,
Phenyl optionally substituted with carboxy, (O2-a,)-alkoxycarbonyl or nitro, (b)(0
2-0,) carboxyalkyl, (vn) (o2-
il,) carbamoyl alkyl, trace> (02-05)
cyanoalkyl, (b)(0,-0,)acetylalkyl, (X)(07-'u)benzoalkyl, optionally with 1.2.3 chloros, (a,-o,) optionally substituted with alkyl, hydroxy, (o, -o,)-alkoxy, carboxy, (02-0,)alkoxycarbonyl, or nitro, (6) pyridyl, optionally 1, 2 or 3 (xlj-)(R6-a,)pyridylalkyl optionally substituted with chloro, (o, -os)alkyl, or (0°-C3)alkoxy, optionally 1.2 , or one that may be substituted with 3 chloro, (01'5) alkyl,
(xiii) (0°-04) hydroxyalkyl 7 □
□□) (0,-,0,)dihydroxyalkyl, (
b) (0, -R4) ) dihydroxyalkyl, provided that R6 and R52 do not contain more than one hydrogen or alkyl) (b) Pyrrolidino, piperidino, morpholino , piperazino, hexamethyleneimino, pyrodine, or 3,4-didehydropiperidinyl containing one or two (0,'
+2) cycloamino selected from the group consisting of optionally substituted with alkyl; (c) R5K is hydrogen or (o, -R4) alkyl, and R5, is other than hydrogen; −F defined σ
] carbonylamino of formula -NR5,COR, where (a) n and Rsh are as defined in (c) % formula % (θ) where R2 and R3 are hydrogen or (CI '4) Alkyl, the same or different, CH2NL2L, or N. Pharmacologically acceptable acid addition sites when is -0H2NL2L, (f) -0021,, (g) OH20HN (h) -0ONR5R,, (t) -OH2-NR5R6 or (j) -0ONH8020H , and M is cis or trans-〇H-OH-(0H2)In-1-(OH2)
n-1-(OH2)n, -0F2-1-00-(CH
2) , -0H2-, trans (Cj H2),
OH-Cj H-1-0H=QH-(OH2)nee,
-0F2-1 or -00-(OH2), -01F2-, L is α-OH:β-H, #OH, or oxo,
R is hydrogen, hydroxy, or methyl, and E is trans-0H-OH-1-0H2-OH2-1 or -〇-
〇-, Q is α-OH: β-R, α-R2: β-OH, or oxo, A is α-H1β-CH5, α-0H5: β-H; α-
H: β-H, α-F, β-F or α-H1β-CHs, R7 is 1) -(0H2), -OH,,2) cis-0H-OH-OH2-OH,,3) (CH2)
20miOHs 4) (CH2) , -〇H-0
(OH,)2, or 5) -0(R,R4)-(C+H
2) g-OH2R,4, R2 is hydrogen or methyl, R5 and R4 are the same or different and are hydrogen or methyl, R5 and R6 are the same or different and are hydrogen, methyl or ethyl, R54 is hydrogen or (a, -R4) alkyl, g is an integer of 1 to 4, m is an integer of 3 to 5, n is an integer of 5 to 7, p is an integer of 1 to 6 is an integer] or N is -0
ONR, , So, R5, is a pharmacologically acceptable salt thereof that is effective in treating or preventing protomia in animals suffering from protomia or CLAIMS 1. A method of treating or preventing non-growth-related proforamia in an animal suffering from or susceptible to heather proforamia, comprising systemic administration to the susceptible animal. 2, N, is -002R,, M, is -OH-0H-(OH
,),! l- or = (OH2)ゎ-1L, is oxo, R
6 is hydroxy, Q is α-OH:β-R2, and A
, is α-H:β-H. 3, Ml is -OH-OOH-0H-(OH2), is trans-0H-OH-1 and R2 is -(a H2) p
The method according to claim 2, which is aHs or cis-0H-OH-OH2-OH. 4. The method according to claim 3, wherein the method of administration is oral. 5. The method according to claim 4, wherein the animal is a human. 6. The method according to claim 5, wherein the compound is PGE1. 7. Preparation with known anti-osteoporosis agents selected from the group consisting of anabolic steroids, estrous steroids, vitamin D and its metabolites, phosphorus-containing agents, pTH% inorganic fluoride-containing agents, calcium salts, and calcitonin. In the method for preventing or treating porosiasis, together with the above-mentioned known antiosteoporosis agent or its wI number,
A method comprising simultaneously administering to a mouse a compound of formula (all variables as defined in claim 1) effective for treating or preventing protomia as described above. 8. For hormonal disease, use anabolic steroids, estrous steroids, vitamin D1 and its substitutes, phosphorus-containing agents, PTH. In a unit dosage form of a pharmaceutical composition for prevention or treatment with one or more known antiosteoporosis agents selected from the group consisting of inorganic fluoride-containing agents, calcium salts, and calcitonin, the formula I [ wherein all variables are as defined in claim 1, in combination with the above known anti-osteoporosis agent or a plurality of these agents to treat or prevent the above-mentioned osteoporosis. An improvement to make Sabajima a unit dosage effective for the treatment. 9. Systemically administering to the animal exhibiting a fracture an amount of a prostaglandin of formula I, in which all variables are as defined in claim 1, effective to increase the rate of fracture healing. A method of increasing the rate of fracture healing in an animal as described above. 10. Systemically administering to an animal in need of bone grafting an amount of a compound of formula I, in which all variables are as defined in claim 1, effective to increase the success rate of bone grafting. A method of increasing the success rate of bone grafting consisting of administering 11. In animals suffering from dental diseases, the compound of formula I (in which all variables are as defined in claim 1) is used to enhance the reorganization and/or integrity of alveolar ligaments to the teeth. A method for enhancing the reconstruction and/or healing of a tooth wISIt, comprising systemically administering a ligament effective for. 12. The compound of formula I is PGIIG, 2-vdecarboxy-12-hydroxymethyl-PGK
,,PGE2. 15-keto-PG[. 16.16-Simethyl-PGM2. 178.20-dimethyl-6-oxo-PGM, methyl ester, 173.20-dimethyl-trans-delta-2-P
GIU,, PGE2, N-methanesulfonylamide, 9-deoxo-9-methylene-16,16-simethyl-PGE. (15s)-15-methyl-PG]1C1(15R)
-15-methyl-PGK2.11-deoxy-16,
16-cymethyl-PGM2.11-deoxy-11α-
16,16-)limethyl-PG]Ic2. 6-oxo-11-deoxy-11α, 16.16-
) Remethyl-PGE2. 6-oxo-PGE2, 6-oxo-PGE, 2-decarboxy-2-hydroxymethyl-PGM,
11-deoxy-15-methyl-PGE,, PGI1
1. ．． 16.16-difluoro PGXi 2 and 20-impropylidene-PGIC, the method of claim 1.7.9.10.